Human DNA polymerase is composed of two subunits, a 140 kDa catalytic subunit encoded by the POLG on chromosome 15q25, and a 55kDa accessory subunit encoded by the POLG2 gene on chromosome 17q23-24.

A number of mutations have been mapped to the gene for the catalytic subunit of DNA polymerase, POLG, and found to be associated with mitochondrial diseases.

This database lists all known mutations in the coding region of the POLG gene and describes the associated disease. This list is maintained by the Mitochondrial DNA Replication Group at NIEHS.

The nucleotide changes are numbered from the initiation Methionine codon and are based on the cDNA (accession U60325.1) and gene sequence (accession AF497906.1).

All inquiries, additions to the list, and comments should be made to Bill Copeland.

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Amino Acid Substitution: R3P cDNA Position: 8 g→c (exon 2)
Disease	Genetics	Frequency	Reference
PEO	ar	(Van Goethem et al., 2001) reported 0 out of 229 control Individuals (<0.4%)	(Van Goethem et al., 2001) PubMed

Amino Acid Substitution: G11D cDNA Position: 32 g→a (exon 2)
Disease	Genetics	Frequency	Reference
Ataxia Neuropathy	Found in cis with R627Q and in trans with R852C, and also found as a Heterozygous mutation with a failure to thrive		(Wong et al., 2008) PubMed
Alpers	Found in cis w/ R852C and in trans w/ W748S. In a second pt. found in cis w/R852C and in trans w/ A467T.		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed
Alpers	Found in cis w/ R852C and in trans w/ A467T. In a 2nd pt., found in cis w/ R852C and in trans w/ W748S and E1143G		(Stewart et al., 2009) PubMed
Leigh Syndrome	Found in cis with R852C and in trans with W748S		(Naess et al., 2009) PubMed
Multiple system atrophy	Found with R852C in a 58 y.o. female with progressive cerebellar atrophy. Pt. had mtDNA deletions and mtDNA depletion.		(Mehta et al., 2011) PubMed
Seizures and liver failure	Found in trans w/ A467T and in cis w/ R852C in an 8 mo. w/ seizures, liver failure, and lactic acidosis.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Encephalopathy	Found in cis w/ R852C and in trans w/ R627Q in a 25 y.o. w/ dementia, encephalopathy, and stroke.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: P18S cDNA Position: 52 t→g (exon 2)
Disease	Genetics	Frequency	Reference
Neutral polymorphism		0.6% of 450 individuals	(GeneSNPs, 2004) PubMed

Amino Acid Substitution: S28C cDNA Position: 82 a→t (exon 2)
Disease	Genetics	Frequency	Reference
PEO	Found in a 25 y.o. pt. that is homozygous for the W748S mutation with PEO, ataxia, ptosis, and hearing loss	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: R42X cDNA Position: 125 del (exon 2)
Disease	Genetics	Frequency	Reference
	Reference # rs59510277		PubMed

Amino Acid Substitution: ±Gln at aa 43-52 cDNA Position: ±(CAG)n at nucleotides 126 to 157 (exon 2)
Disease	Genetics	Frequency	Reference
Male infertility	Identified an association between absence of the common, ten CAG repeat allele and male infertility due to a range of sperm quality defects.	Rovio et al., 2001 reported 88% of both Finnish and ethnically mixed populations carry the predominant allele of 10 CAG repeats	(Rovio et al., 2001) PubMed
Male infertility	Predictive value for infertility in a man homozygous for the POLG CAG polymorphism was 15.5% (95% CI: 4.8-51%). There was a positive association with sperm concentration.	Studied in 1298 male subjects: 429 patients with infertility/subfertility, and 869 controls (495 men from the general population with unknown fertility and 374 recent fathers)	(Jensen et al., 2004) PubMed
	The human DNA POL gamma is unique in that the first exon of the gene contains a CAG10 trinucleotide repeat.		(Ropp and Copeland, 1996)  PubMed
Male infertility	Micro-deletion in the Y chromosome frequency in France, averaged: 10–15% in cases of azoospermia, and 5–10% in cases of oligozoospermia.		(Aknin-Seifer et al., 2005) PubMed
Male infertility	Suggested that the POLG1 CAG-repeat polymorphisms does not contribute to oligozoospermia in French and Italian populations.	625 individuals in three groups of case-controls from three different Italian regions	(Brusco et al., 2006) PubMed
Male infertility	80 normozoospermic and 124 non-normozoospermic semen samples were analyzed for nucleotide substitutions. There were no significant differences in the frequencies of nucleotide substitution and POLgamma genotypes in the two groups.		(Harris et al., 2006) PubMed
Male infertility	The mutated genotype was found at the same frequency in both infertile and normospermic Italian men.		(Krausz et al., 2004) PubMed
Frequency study	The heterozygosity level ranges from 22% in Europe to 13.6% in Southwest Asia with the lowest value of 7.4% in Siberia/East Asia. Found an extremely low variability of the trinucleotide CAG microsatellite repeats.	The population sample consisted of 1,330 individuals from 3 large geographic areas: Europe, Southwest Asia, and Siberia/East Asia.	(Malyarchuk et al., 2005) PubMed
Testicular cancer	Studied CAG repeat length variation at the POLG gene locus in a group of patients with testicular tumors compared with an equivalent healthy Polish male population. The CAG repeats in the POLG gene were significantly more frequent in testicular cancer pat	Nowak et al., 2005 reported 11% healthy Polish men (n=55) were heterozygous, and 26% of testicular cancer patients (n=49) were heterozygous for the CAG repeats ÅÇ 10. With no clinical differences in tumor pathology	(Nowak et al., 2005) PubMed
Idiopathic sporadic Parkinson	Increase frequency of non-10/11 (CAG) variant in Parkinson disease (PD)	Luoma, 2007: found in 10% PD patients compared with 3.5-4.3% spouse/population controls.	(Luoma et al., 2007) PubMed
Seminoma testicular cancer	Homozygous lack of 10 CAG repeat	4.9% of Danish men (n=869). 96.7% of Seminoma pts.	(Jensen et al., 2008) PubMed
Friedreich's Ataxia	Age of onset of FRDA is inversely correlated to the POLG CAG repeats	Study done in 49 Iranian FRDA pts.	(Heidari et al., 2008) PubMed
Sporadic Parkinson	CAG repeat region screened in 243 Swedish Parkinson’s pts. An assoc. was found with repeats in glutamine runs that were not 10 or 11 in number.	243 Swedish PD patients and 279 Swedish controls	(Anvret, et al., 2010) PubMed
PEO and ovarian failure	Compound heterozygote found w/ K947R		(Baruffini et al., 2011) PubMed
10/11Q	10/11Q found in a Chinese population with Parkinsonism at a frequency of 86.9% compared to the controls at 93.5% and non 10/11Q runs were found at 13.1% in PD pts and 6.5% in controls.	344 Chinese parkinson patients and 144 controls	(Gui et al., 2012) PubMed
	This study was a meta-analysis of 13 other published works and the overall result was that the CAG repeats did not affect male fertility.		(Zhang et al., 2016) PubMed

Amino Acid Substitution: Q43R cDNA Position: 128 a→g (exon 2)
Disease	Genetics	Frequency	Reference
Idiopathic sporadic Parkinson			(Luoma et al., 2007) PubMed
	Reference # rs28567406		PubMed

Amino Acid Substitution: Q44X cDNA Position: 132 del gc (exon 2)
Disease	Genetics	Frequency	Reference
	Reference # rs35424491		PubMed

Amino Acid Substitution: Q45R cDNA Position: 134 a→g (exon 2)
Disease	Genetics	Frequency	Reference
Epilepsy	Found in trans w/ D136E	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed

Amino Acid Substitution: Q49E cDNA Position: 145 c→g (exon 2)
Disease	Genetics	Frequency	Reference
	Neutral polymorphism	<1 % in control populations	(Luoma et al., 2007) PubMed

Amino Acid Substitution: Q49X cDNA Position: 147 del gc (exon 2)
Disease	Genetics	Frequency	Reference
	Reference # rs72434227		PubMed

Amino Acid Substitution: Q50X cDNA Position: 149 del ag (exon 2)
Disease	Genetics	Frequency	Reference
	Reference # rs71879812		PubMed

Amino Acid Substitution: Q53X cDNA Position: 158 del aa (exon 2)
Disease	Genetics	Frequency	Reference
	Reference # rs41550117		PubMed

Amino Acid Substitution: Q53Pfs cDNA Position: 150_ 158delGCAGCAGCA (exon 2)
Disease	Genetics	Frequency	Reference
Hepaticencephalopathy, Alpers-Huttenlocher	Found as compound heterzygous in trans with R227Q in a two year old girl.		(Dai et al., 2019) PubMed

Amino Acid Substitution: Q53-Q55dup cDNA Position: 158 dup cag (exon 2)
Disease	Genetics	Frequency	Reference
PEO	Found in trans w/R964C in an 8 y.o. male with recessive ataxia, PEO, and hyoptonia		Ohba et al., 2013 PubMed

Amino Acid Substitution: S64L cDNA Position: 191 c→t (exon 2)
Disease	Genetics	Frequency	Reference
Charcot-Marie-Tooth	Found in cis with R232H in ar Charcot-Marie-Tooth	30.6% of control population (90/294 control alleles)	(Harrower et al, 2008) PubMed

Amino Acid Substitution: Q68X cDNA Position: 202 c→t (exon 2)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans w/ A467T		(Wong et al., 2008) PubMed

Amino Acid Substitution: L79F cDNA Position: 235 c→t (exon 2)
Disease	Genetics	Frequency	Reference
Epilepsy	Found in compound with S1080I in an 8 yo female with adrenocortical insufficiency and hypothyroidy	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
Epilepsy	Found in compound with S1080I in an 8 yo female with epilepsy, cerebellar ataxia, and ptosis	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed

Amino Acid Substitution: L83P cDNA Position: 248 t→c (exon 2)
Disease	Genetics	Frequency	Reference
Alpers	Compound heterozygous mutation with G888S in 10 yr. old		(Bao et al., 2008) PubMed
			(Wong et al., 2008) PubMed

Amino Acid Substitution: F88L cDNA Position: 264 c→g (exon 2)
Disease	Genetics	Frequency	Reference
	Found in trans w/ A467T in a 42 y.o. w/ no symptoms noted	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed
Progressive cavitating leukoencephalopathy	Found as homozygous in a 2 year-old girl with intermittent motor deficits which partially resolved over several months.		(Shinagawa et al., 2020) PubMed

Amino Acid Substitution: H110Y cDNA Position: 328 c→t (exon 2)
Disease	Genetics	Frequency	Reference
PEO	Found as a heterozygous mutation in a and Complex I deficiency in a child from South India		(Sonam et al., 2017) PubMed
	Heterozygous, hypotonia, failure to thrive, short stature, respiratory failure		(Wong et al., 2008) PubMed

Amino Acid Substitution: W113G cDNA Position: 337 t→g (exon 2)
Disease	Genetics	Frequency	Reference
	Reference # rs77321104		PubMed

Amino Acid Substitution: P116Q cDNA Position: 347 c→a (exon 2)
Disease	Genetics	Frequency	Reference
	Found in compound w/ T251I and P587L in an Italian 8 y.o. female with fatigue,hypotonia, and delayed psychomotor development with no mtDNA depletion. Diabetic father was positive for P116Q and the deaf mother was positive for T251I and P587L.	0 found in 200 chromosome controls	(Scuderi, et al., 2015) PubMed
	Found in compound w/ T251I andP587L in an Italian 14 y.o. male with fatigue,hypotonia, left eye ptosis, migrains, but normal cognitive skills. Diabetic father was positive for P116Q and the deaf mother was positive for T251I and P587L.	0 found in 200 chromosome controls	(Scuderi, et al., 2015) PubMed

Amino Acid Substitution: D122Y cDNA Position: 364 g→t (exon 2)
Disease	Genetics	Frequency	Reference
Sensory axonal neuronopathy	Found in a 67 y.o. female and her 61 y.o. brother. Found in compound w/Y837C, K601E, Q1236H. Both patients have an ataxia, dysarthria, seizures, and sensory neuropathies.	Not found in 200 chromosome controls	(Zabalza et al., 2014) PubMed

Amino Acid Substitution: D136E cDNA Position: 408 c→g (exon 2)
Disease	Genetics	Frequency	Reference
Epilepsy	Found in trans w/ Q45R	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed

Amino Acid Substitution: A143V cDNA Position: 427 g→t (exon 2)
Disease	Genetics	Frequency	Reference
Alpers		Sarzi et al. 2007 reported 2% (n=50) of patients with multiple respiratory chain deficiency with a 35% decrease of mtDNA	(Sarzi et al. 2007) PubMed
PEO	Found in trans w/ L304R in a 22 y.o. pt. with PEO and cerebral cavernous malformation.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ G848S in a 4 y.o. w/ hypotonia, encephalopathy, seizures, hepatic failure, and developmentally delayed	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ G848S in a 38 y.o. w/ ataxia, peripheral neuropathy, hearing loss, and seizures	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ A467T in an 8 y.o. w/ seizures and an abnormal MRI	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans w/ G848S in a 37 y.o. symptoms not noted	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found in trans w/ A467T in a 49 y.o. w/ PEO, encephalopathy, ataxia, seizures, neuropathy, hearing loss, and muscle weakness	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found in compound w/W748S and E1143G in a 40 y.o. female patient w/ chronic intestinal pseudo-obstruction, PEO, and ataxia.	In 5 out of 80 patients w/ chronic intestinal pseudo-obstruction	(Amiot et al., 2009) PubMed

Amino Acid Substitution: P163S cDNA Position: 487 c→t (exon 2)
Disease	Genetics	Frequency	Reference
Opthalmoplegia and seizures	Found in trans w/T851A in a 21 y.o. female with peripheral neuropathy, seizures, dysarthria and bilateral ptosis	1 in 322 mitochondrial disease patients	(Woodbridge et al., 2012) PubMed

Amino Acid Substitution: P163L cDNA Position: 488 c→t (exon 2)
Disease	Genetics	Frequency	Reference
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: E183X cDNA Position: 547 del g (exon 2)
Disease	Genetics	Frequency	Reference
	Reference # rs35065786		PubMed

Amino Acid Substitution: R193Q cDNA Position: 578 g→a (exon 2)
Disease	Genetics	Frequency	Reference
Neutral polymorphism		0.6% of 450 individuals	(GeneSNPs, 2004) PubMed
	Reference # rs3176162		PubMed

Amino Acid Substitution: A194V cDNA Position: 580 g→t (exon 2)
Disease	Genetics	Frequency	Reference
Inclusion body myositis	Found as a heterozygous mutation in a Swedish patient with Inclusion body myostitis. In addition the patient had COX deficient muscle fibers, ragged red fibers, and mtDNA deletions.	1 in 26 patients with inclusion body myositis. 8 of which had heterozygous POLG mutations.	(Lindgen et al., 2015) PubMed

Amino Acid Substitution: F197S cDNA Position: 590 t→c (exon 2)
Disease	Genetics	Frequency	Reference
Myopathy, PEO, and Ptosis	Found as compound heterozygous in trans with T914P in a 69 year-old man with slowly progressive bilateral ptosis and severely reduced horizontal and vertical gaze.		( Hedberg-Oldfors et al., 2020) PubMed

Amino Acid Substitution: C224Y cDNA Position: 671 g→a (exon 3)
Disease	Genetics	Frequency	Reference
Alpers		Sarzi et al. 2007 reported 2% (n=50) of patients with multiple respiratory chain deficiency with a 35% decrease of mtDNA	(Sarzi et al. 2007) PubMed

Amino Acid Substitution: R227W cDNA Position: 679 c→t (exon 3)
Disease	Genetics	Frequency	Reference
PEO	36% of patients with sporadic PEO with multiple mtDNA deletions carry mutations in one of the three genes associated with familial arPEO or adPEO. Twinkle gene in 7% and POLG1 gene in 25% of our Italian and British patients with sporadic PEO. Found as c	7 out of 27patients w/sporadic PEO compared to 250 controls individuals.	(Agostino et al., 2003) PubMed
PEO	Found as compound in trans w/ S1176L.  Also, found as compound in trans with T251I-P587L.		(Lamantea and Zeviani, 2004) PubMed
Alpers, Severe childhood multi-system disorder	In Alpers found as compound with A467T. In severe childhood multi-system disorder found as compound with D1184N	de Vries et al. , 2007 identified 1 (4.76%) children out of 21 with a POLG mutation that were known to have a mitochondrial disorder	(de Vries et al., 2007) PubMed
Myopathy and gastrointestinal obstruction	Found in trans w/ G848S with mtDNA depletion and Cox deficient muscle fibers		(Giordano et al., 2009) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: R227P cDNA Position: 680 g→c (exon 3)
Disease	Genetics	Frequency	Reference
Severe childhood multi-system disorder	Compound heterozygous with A467T	de Vries et al. , 2007 identified 1 (4.76%) children out of 21 with a POLG mutation that were known to have a mitochondrial disorder	(de Vries et al., 2007) PubMed
Epilepsy and failure to thrive	Found in trans w/ A467T	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed

Amino Acid Substitution: R227Q cDNA Position: 680 g→a (exon 3)
Disease	Genetics	Frequency	Reference
Lethal MDS	Found one heterzygous female neonate in trans with A1033V. The baby died at the age of 5 months.		(AlJabri et al., 2018) PubMed
Hepaticencephalopathy, Alpers-Huttenlocher	Found as compound heterzygous in trans with Q53Pfs in a two year old girl.		(Dai et al., 2019) PubMed

Amino Acid Substitution: R232G cDNA Position: 694 c→g (exon 3)
Disease	Genetics	Frequency	Reference
Infantile Hepatocerebral Syndrome	Found as compound with T251I and P587L	Ferrari et al., 2005 reported 1 in 9 (11.11%) children with a combination of progressive neurological and hepatic failure, with an allelic frequency of <0.14% (0 out of 350) in the control group.	(Ferrari et al., 2005) PubMed
Alpers	Found in trans w/ [T251I and P587L]		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed
Hepatocerebral MDS	Found in trans w/ [T251I andP587L]		(Spinazzola et al., 2009) PubMed

Amino Acid Substitution: R232H cDNA Position: 695 g→a (exon 3)
Disease	Genetics	Frequency	Reference
Liver failure, encephalopathy, and epilepsy	Found as compound in trans with W748S - E1143G	Not found in 200 control alleles	(Kollberg et al., 2006) PubMed
Charcot-Marie Tooth disease, (CMT) (profound cerebellar ataxia)	Found in cis with the S64L SNP and in trans with G737R	Not detected in 282 control alleles	(Harrower et al, 2008) PubMed
Leigh Syndrome	In trans w/G848S		(Taanman et al, 2008) PubMed
Infantile hepatocerebral	Found in trans w/A467T and in cis w/H277L in a 2 mo. mold w/hypotonia, motor paresis and developmentally delayed		(Hunter et al., 2011) PubMed
Infantile hepatocerebral	Found in trans w/A467T and in cis w/H277L in a 1.5 mo. old w/hypotonia and developmentally delayed		(Hunter et al., 2011) PubMed
Infantile hepatocerebral	Found W748S and E1143G w/ A467T in a pediatric patient w/mitochondrial encephalomyopathy, seizures, ataxia, and ophthalmological involvement		(Sofou et al., 2012) PubMed
Parkinsonism	Found as a heterozygous mutation in a 25 yo male with sensorimotor neuropath, ataxia, and mtDNA deletions	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
Sensorimotor neuropathy	Found as a heterozygous mutation in a 30 yo female with axonal sensorimotor neuropathy	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
Sensorimotor neuropathy	Found as a heterozygous mutation in a 20 yo female with sensorimotor neuropath ,and ataxia	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
SANDO	Found in trans w/T251I/P587L and in cis w/H277L in a 26 y.o. with PEO, cognitive impairment, ataxia, polyneuropathy, muscle weakness, migraines, dysphagia, and dysarthria.		(Bereau et al., 2016) PubMed
SANDO	Found in trans w/T251I and P587L and in cis w/H277L in a 40 y.o. with PEO, ataxia, polyneuropathy, and dysarthria.		(Bereau et al., 2016) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: W235X cDNA Position: 705 g→a (exon 3)
Disease	Genetics	Frequency	Reference
Severe childhood multi-system disorder	Found as compound heterozygote with A467T	de Vries et al. , 2007 identified 1 (4.76%) children out of 21 with a POLG mutation that were known to have a mitochondrial disorder	(de Vries et al., 2007) PubMed

Amino Acid Substitution: Q238R cDNA Position: 713 a→g (exon 3)
Disease	Genetics	Frequency	Reference
	Reference # rs56410699		PubMed

Amino Acid Substitution: P241L cDNA Position: 722 c→t (exon 3)
Disease	Genetics	Frequency	Reference
Neutral polymorphism		<1 % in control populations	(Luoma et al., 2007) PubMed
Parkinsonism	Found in a Chinese population with Parkinsonism at an allelic frequency of 0.326	344 Chinese parkinson patients and 144 controls	(Gui et al., 2012) PubMed

Amino Acid Substitution: L244P cDNA Position: 731 t→c (exon 3)
Disease	Genetics	Frequency	Reference
Infantile Hepatocerebral Syndrome	Found as compound with W748S	1 in 9 (11.11%) children with a combination of progressive neurological and hepatic failure, with an allelic frequency of <0.14% (0 out of 350) in the control group.	(Ferrari et al., 2005) PubMed
Alpers	Found 2 infants in trans with W748S		(Spinazzola et al., 2009) PubMed

Amino Acid Substitution: T251I cDNA Position: 752 c→t (exon 3)
Disease	Genetics	Frequency	Reference
PEO	ar PEO. Found as compound with R309L, or 2354G insertion, or G848S in PEO.	1 in 9 (11.11%) children with a combination of progressive neurological and hepatic failure, with a heterozygous frequency of 1% of Italian controls.	(Ferrari et al., 2005) PubMed
PEO	Found in compound with R807P		(Del Bo et al., 2003) PubMed
Infantile Hepatocerebral Syndrome	Frequently found in cis with P587L and compound in trans with L304R, V1106I, and R227W .	Not found in 250 control individuals	(Horvath et al., 2006) PubMed
PEO	Found as compound in trans w/ S1176L, G848S, G785X, V1106I, R309L and R227W and cis w/ P587L.  Also, T251I/P587L was found as a homozygous mutation.		(Lamantea and Zeviani, 2004) PubMed
PEO and mtDNA deletions	Found in compound w/P587L/ R807P in1 pt. and w/P587L/ H932Y in a 2nd pt. A 3rd pt. was found in compound w/P587L only. The study includes 31 mitochondrial myopathy patients w/ mtDNA deletions.	31 mitochondrial myopathy patients without any family history for the disorder	(Di Fonzo et al., 2003) PubMed
Infantile Hepatocerebral Syndrome	36% of patients with sporadic PEO with multiple mtDNA deletions carry mutations in one of the three genes associated with familial arPEO or adPE. Twinkle gene in 7% and POLG1 gene in 25% of our Italian and British patients with sporadic PEO. Found as co	7 out of 27patients w/sporadic PEO compared to 250 controls individuals.	(Agostino et al., 2003) PubMed
MNGIE	Found in cis with P587L and in trans w/N846S.	Van Goethem, 2003: Not found in 280 control chromosomes	( Van Goethem et al., 2003c)  PubMed
Infantile Hepatocerebral Syndrome	Found in 1 of 9 infantile hepatocerebral syndrome patients. In cis with P587L and compound with R232G.	9 infantile hepatocerebral patients of German and Italian descent.	(Ferrari et al., 2005) PubMed
PEO	POLG molecular defects were found in 25% of patients with multiple mtDNA deletions and mitochondrial disease. Found in trans w/M603L and in cis with P587L.	24 patients diagnosed with mitochondrial disease and having multiple mtDNA deletions compared to 100 controls in a Spanish population.	(Gonzalez - Vioque et al., 2006)  PubMed
PEO	Found in trans w/ G848S and in cis w/ P587L in a 75 y.o. male.		(Kollberg et al., 2005) PubMed
Alpers	Found in trans w/ G848S and in cis w/ P587L. Also found in cis w/P587L and in trans w/R853Q in myocerebralhepatopathy patient. Also found as a heterozygous mutation with ataxia, ptosis, and neuropathy.		(Wong et al., 2008) PubMed
Alpers	Found in cis w/ R232G and cis w/ P587L.		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed
PEO	Found in cis w/ P587L, with both mutations on each allele. A 2nd pt. found to have P587L in trans and A467T in cis.		(Stewart et al., 2009) PubMed
mtDNA depletion	In cis w/P587L and in trans w/ E1136K		(Taanman et al., 2008) PubMed
Hepatocerebral MDS	Found in cis with P587L and in trans with R232G		(Spinazzola et al., 2009) PubMed
Restless leg syndrome, ptosis, diplopia, limb weakness, blurred vision	Found in trans with P587L.		(Aitken, et al., 2009) PubMed
PEO	Found in trans with W748S andP587L		(Tzoulis, et al., 2009) PubMed
PEO and mental retardation	Found in cis w/P587L and in trans w/ R275X	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed
PEO, exercise intolerance, diabetes and a 2nd pt. w/ cataract and myopathy	Found in cis w/P587L and in trans w/ A467T	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Ptosis	Found in cis w/P587L and in trans w/ G848S	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Epilepsy and mental retardation	ad, Found w/P587L	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Seizures, hypotonia, and developmental delay	Found w/P587L		(Burusnukul and de los Reyes, 2009) PubMed
Acute disseminated encephalomyelitis	Found w/P587L, found in one 4 y.o. patient with autoimmune central nervous system disease		(Harris et al., 2010) PubMed
SANDO	Found sporadically w/P587L and G848S in a 80 y.o. male		(Wiess and Saneto, 2010) PubMed
Ptosis and myopathy	Found in cis with P587L and in trans with P648R in a 59 y.o. male with dysphagia, dysphonia, myopathy, ptosis, and mtDNA deletions. Father had same symptoms.		(Ferreira et al., 2011) PubMed
PEO	Found in cis w/ P587L and in trans w/ H932Y in a 31 y.o. w/ neuropathy, PEO, ptosis, and COX deficiency.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Peripheral Neuropathy	Found in cis w/ P587L and in trans w/ H932Y in a 40 y.o. w/ peripheral neuropathy, ptosis, and muscle weakness.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found in cis w/ P587L and in trans w/ G848S in an 80 y.o. w/ peripheral neuropathy, ptosis, and abnormal muscle histology	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found in cis w/ P587L and in trans w/ K1191N in a 39 y.o. w/ PEO, neuropathy, ptosis, and muscle weakness	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in cis w/ P587L and in trans w/ N1157S in a 9 y.o. Symptoms not noted	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans w/ G588D and in cis w/ P587L in a 6 y.o. w/ no symptoms noted	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found in compound with G848S in a 45 yo female with mtDNA deletions	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
SANDO	Found in cis with P587L and in trans with A467T in a female in her 60's with a 5 year history of peripheral neuropathy, blurred vision, unstable gait, and sensory ataxia, dementia, and ophthalmoplegia.		(Lovan et al., 2013) PubMed
SANDO	Found in cis w/P587L and in trans w/R869Q in a 34 y.o. female with ataxia, ptosis, diabetes and mtDNA deletions.		(Hanisch et al., 2014) PubMed
PEO	Found in compound w/P587L and D1184N in a 33 y.o. female patient w/ chronic intestinal pseudo-obstruction, PEO, and ataxia.	In 5 out of 80 patients w/ chronic intestinal pseudo-obstruction	(Amiot et al., 2009) PubMed
PEO	Found in compound w/P587L and D1184N in a 30 y.o. male patient w/ chronic intestinal pseudo-obstruction and PEO.	In 5 out of 80 patients w/ chronic intestinal pseudo-obstruction	(Amiot et al., 2009) PubMed
	Found in compound w/ P116Q and P587L in an Italian 8 y.o. female with fatigue,hypotonia, and delayed psychomotor development with no mtDNA depletion. Diabetic father was positive for P116Q and the deaf mother was positive for T251I and P587L.	0 found in 200 chromosome controls	(Scuderi, et al., 2015) PubMed
	Found in compound w/ P116QI andP587L in an Italian 14 y.o. male with fatigue,hypotonia, left eye ptosis, migrains, but normal cognitive skills. Diabetic father was positive for P116Q and the deaf mother was positive for T251I and P587L.	0 found in 200 chromosome controls	(Scuderi, et al., 2015) PubMed
Parkinsonism and PEO	Found in cis w/P587L and in trans w/W468X. Found in a 68 y.o. female w/ exercise intolerance, PEO, facial diparesis, and left-dominant postural tremor.		(Miguel, et al., 2014) PubMed
PEO	Found in cis with P587L and in trans w/W748S in a 50 y.o.with PEO and myopathy. In a study that suggests that dopaminergic neurons are vulnerable to the accumulation of somatic mtDNA damage, and defects of mtDNA replication and repair.		(Tzoulis et al., 2016) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in trans w/G848S and in cis w/P587L with PEO, muscle weakness, and cognitive impairment. Similar to SANDO, but no dysarthria.		(Bereau et al., 2016) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in trans w/S1095R and in cis w/P587L with PEO, muscle weakness, ataxia, and polyneuropathy. Similar to SANDO, but no dysarthria.		(Bereau et al., 2016) PubMed
SANDO	Found in cis w/P587L and in trans w/R232H and H277L in a 26 y.o. with PEO, cognitive impairment, ataxia, polyneuropathy, msucle weakness, migraines, dysphagia, and dysarthria.		(Bereau et al., 2016) PubMed
PEO	Found in cis with P587L and in trans w/A467T in a 30 y.o. with muscle weaknes and PEO.		(Bereau et al., 2016) PubMed
SANDO	Found in cis w/P587L and in trans w/R232H and H277L in a 40 y.o. with PEO, ataxia, polyneuropathy, and dysarthria.		(Bereau et al., 2016) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in trans w/R852C and in cis w/P587L in a 50 y.o. with PEO, muscle weakness, and polyneuropathy. Similar to SANDO, but no dysarthria.		(Bereau et al., 2016) PubMed
PEO	Found in trans w/A467T and in cis w/P587L in a 56 y.o. with PEO, muscle weakness, and dysphagia.		(Bereau et al., 2016) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in trans w/A467T and in cis w/P587L in a 58 y.o. with ataxia, sensory neuropathy, and dysphagia.		(Bereau et al., 2016) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in trans w/A467T and in cis w/P587L in a 66 y.o. with ataxia, sensory neuropathy, and PEO.		(Bereau et al., 2016) PubMed
PEO	Found in cis w/P587L on both allesls with ptosis and dysphagia		(Bereau et al., 2016) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in trans w/T251I and P587L with ataxia, sensory neruopathy, PEO, deafness, and dysphagia.		(Bereau et al., 2016) PubMed
PEO	Found in cis with P587L and in trans w/T989dup in a 36 y.o. female with cornieal edema and muscle weakness. One brother affected and has both variants and one unaffected sister with no mutations.	Not found in 100 random controls	(Pozzo et al., 2017) PubMed
Neuropathy w/ cataracts and glaucome	Found in trans with R943C and in cis withP587L in an 8 mo. female with uppper and lower limb distal neuromyopathy with ragged red fiberes, cataracts. Later developed ophthalmoparesis, glaucoma, and muscle wasting.		(Castiglioni et al., 2018) PubMed
Neuropathy w/ cataracts and glaucome	Found in trans with R943C and in cis withP587L in an 24 mo. female with uppper and lower limb distal neuromyopathy with ragged red fiberes, cataracts. Later developed ophthalmoparesis, glaucoma, and muscle wasting.		(Castiglioni et al., 2018) PubMed
Late-onset MDS	Found as compound heterozygous in cis with P587L and in trans with R807C in a 70 year-old man presenting with a late onset sensory neuronopathy, chronic progressive external ophthalmoplegia, gait ataxia and parkinsonism.		(Meira et al., 2019) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: G268A cDNA Position: 803 g→c (exon 3)
Disease	Genetics	Frequency	Reference
PEO	Sporadic / unknown Found as compound in trans with A467T	Di Fonzo 2003: Not found in 100 DNA samples from healthy Italians	(Di Fonzo et al., 2003) PubMed
PEO	Sporadic / unknown Found as compound in trans with A467T		(Del Bo et al., 2003) PubMed
PEO	Sporadic / unknown Found as compound in trans with A467T		(Baruffini et al., 2006) PubMed
PEO	Sporadic / unknown Found as compound in trans with A467T	24 patients diagnosed with mitochondrial disease and having multiple mtDNA deletions compared to 100 controls in a Spanish population.	(Gonzalez - Vioque et al., 2006) PubMed
Parkinsonism, dystonia, mental retardation, hepatocerebral syndrome, ptosis, neuropathy, and intestinal problems	ar, 3 patients ages 3-16 yrs	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed
	Reference # rs61752784		PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: R275X cDNA Position: 823 c→t (exon 3)
Disease	Genetics	Frequency	Reference
PEO and mental retardation	Found in trans w/ T251I+P587L	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed

Amino Acid Substitution: R275Q cDNA Position: 824 g→a (exon 3)
Disease	Genetics	Frequency	Reference
Multiple Sclerosis-like illness and PEO	Found as a heterozygous mutation w/A467T in a 63 y.o. Pt. first diagnosed w/ optic neuritis and MS 33 yrs earlier. Currently, pt. has ragged-red muscle fibers, ptosis, myopathies, PEO, and mtDNA deletions.		(Echaniz-Laguna et al., 2010) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in trans w/A467T in a 62 y.o. with ataxia, sensory neuropathy and PEO.		(Bereau et al., 2016) PubMed

Amino Acid Substitution: H277L cDNA Position: 830 a→t (exon 3)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans w/T851A		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed
Infantile hepatocerebral	Found in trans w/A467T and in cis w/R232H in a 2 mo. old w/hypotonia, motor paresis and developmentally delayed		(Hunter et al., 2011) PubMed
Infantile hepatocerebral	Found in trans w/A467T and in cis w/R232H in a 1.5 mo. old w/hypotonia and developmentally delayed		(Hunter et al., 2011) PubMed
Myelopathy,myopathy, peripheral neuropathy and subcortical grey matter degeneration	Found in trans w/A862T in a 66 y.o. female with mtDNA deletions and subcortical grey matter degeneration		(McKelvie et al., 2012) PubMed
Parkinsonism	Found in trans w/R943C in a 78 y.o. Japanese male with parkinsonism.	Not found in 50 ethnically matched controls	(Sato et al., 2011) PubMed
SANDO	Found in trans w/R232H and in cis w/T251I andP587L in a 26 y.o. with PEO, cognitive impairment, ataxia, polyneuropathy, msucle weakness, migraines, dysphagia, and dysarthria.		(Bereau et al., 2016) PubMed
SANDO	Found in trans w/T251I and P587L and in cis w/R232H in a 40 y.o. with PEO, ataxia, polyneuropathy, and dysarthria.		(Bereau et al., 2016) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: Y282D cDNA Position: 844 t→g (exon 3)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans w/L304R in a patient with intractable convulsions and severe epileptic status.	1 of 52 pediatric patients suspected to have mitochondrial DNA depletion syndrome	(Navarro-Sastre et al., 2012) PubMed
Myoclonus	Found as heterozygous in father and son with Twitching and Stiffness.		(Pauly et al., 2019) PubMed

Amino Acid Substitution: N285H cDNA Position: 855 g→c (exon 3 or 4)
Disease	Genetics	Frequency	Reference
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: R290C cDNA Position: 868 c→t (exon 4)
Disease	Genetics	Frequency	Reference
Epilepsy and devleopmental delay	Found in a 5 month old male with infantile spasms and global developmental delays		(Wang et al., 2017) PubMed

Amino Acid Substitution: M299L cDNA Position: 895 a→c (exon 4)
Disease	Genetics	Frequency	Reference
MNGIE-like syndrome	Found as compound heterozygous in trans with c.3626_3629dupGATA in a 26-year-old male with MNGIE-like syndrome together with leukoencephalopathy and demyelinating neuropathy.		(Yasuda et al., 2019) PubMed

Amino Acid Substitution: G303R cDNA Position: 907 a→g (exon 4)
Disease	Genetics	Frequency	Reference
Encephalopathy	Found in trans w/ A467T in 2 brothers and a 3rd unrelated pt. All 3 had ataxia, epilepsy, and encephalopathy.	Not found in 170 control individuals	(Tzoulis, et al., 2010) PubMed
Alpers	Found in trans w/ A467T in a pediatric patient w/mitochondrial encelphalomyopathy, seizures, ataxia, and ophthalmological involvement		(Sofou et al., 2012) PubMed
Encephalopathy	Found w/A467T in a 9 mo. child w/epilepsy and death at 1.1 yrs.		(Tzoulis et al., 2014) PubMed
Encephalopathy	Found w/A467T in a 2 y.o child w/epilepsy, ataxia, and death at 8.0 yrs.		(Tzoulis et al., 2014) PubMed
Alpers	Found in trans with A467T in one baby		(Hayhurst et al., 2019) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: L304R cDNA Position: 911 t→g (exon 4)
Disease	Genetics	Frequency	Reference
PEO Ataxia - neuropathy	ar  Compound in trans with A467T  Found as homozygous or compound in trans with W748S - E1143G in SCAE, ataxi-neuropathy	Not found in 300 healthy French control chromosomes	(Naimi et al., 2006) PubMed
PEO Ataxia - neuropathy	ar  Compound in trans with A467T  Found as homozygous or compound in trans with W748S - E1143G in SCAE, ataxic-neuropathy		( Stuart et al., 2006) PubMed
Alpers	Found homozygous in one pt.		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed
Alpers	Found in trans w/ L392V and R1081dup.		(Cardenas et al., 2010) PubMed
VPA induced liver toxicity	Found in trans with A467T in a 15 y.o. pt. with VPA induced hepatotoxicity	Used 968 alleles ethnically matched controls	(Stewart et al., 2010) PubMed
Peripheral neuropathy	Found as a homozygote in a 23 y.o. pt. with exercise intolerance, muscle weakness, and ragged red fibers.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ D1145GfsX9 in a developmentally delayed 12 y.o. with seizures and hypotonia.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found in trans w/ G737R in a 54 y.o. w/PEO, ptosis, and muscle weakness	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found as a homozygote in a 12 y.o. w/ PEO, ptosis, neuropathy, and developmentally delayed.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found as a homozygote in a 9 y.o. with PEO, neuropathy, ptosis, and COX deficient fibers.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found as a homozygote in a 2 y.o. pt. w/ encephalopathy, seizures, and developmentally delayed.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found in trans w/ A143V in a 22 y.o. pt. with PEO and cerebral cavernous malformation.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found as a homozygote in a 9 y.o. with ptosis, ataxia, hypotonia, and cerebellar atrophy.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found has a homozygote in a 4 y.o. w/ seizures, ptosis, and an abnormal MRI.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found as a homozygote in a 10 y.o. w/ ptosis, PEO, ataxia, and muscle weakness	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans w/ A467T in a 15 y.o. symptoms not noted	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ R1081dup in a 1 y.o. w/seizures and developmentally delayed	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found in trans w/ R1081P in a 10 y.o. w/ ataxia, seizures, PEO, and dystonia	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Alpers	Found in trans w/G888D in a patient showing psychomotor retardation, epileptic encephalopathy, progressive cerebral atrophy, and altered liver enzymes.	2 of 52 pediatric patients suspected to have mitochondrial DNA depletion syndrome	(Navarro-Sastre et al., 2012) PubMed
Alpers	Found in trans w/Y282D in a patient with intractable convulsions and severe epileptic status.	2 of 52 pediatric patients suspected to have mitochondrial DNA depletion syndrome	(Navarro-Sastre et al., 2012) PubMed
SANDO	Found as a homozygous mutation in a 15 yo male with 40% COX neg muscle fibers and multiple mtDNA deletions	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
PEO	Found in compound with W748S in a 27 yo female with sensory and cerebellar ataxia, axonal sensory neuropathy	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
PEO	Found in trans w/c.1713-21 in a 23 y.o.with PEO, ataxia, and myopathy. In a study that suggests that dopaminergic neurons are vulnerable to the accumulation of somatic mtDNA damage, and defects of mtDNA replication and repair.		(Tzoulis et al., 2016) PubMed
SCAE	Found in trans w/W748S with PEO, cognitive impairment, seizures, ataxia, polyneuropathy, dysphagia, and dysarthria.		(Bereau et al., 2016) PubMed
SANDOS	Found as a homozygous mutation w/ multiple complex deficiencies in a child from South India		(Sonam et al., 2017) PubMed
Ataxia neuropathy	Found as a homozygous mutation w/ multiple complex deficiencies in a child from South India		(Sonam et al., 2017) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: S305R cDNA Position: 915 c→g (exon 4)
Disease	Genetics	Frequency	Reference
Alpers	heterozygous		(Wong et al., 2008) PubMed
Alpers	Found in trans w/A467T	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Alpers	Found as a compound heterozygote w/P1073L.		(Baruffini et al., 2011) PubMed
Epilepsy and ataxia-neuropathy	Heterozygous mutation w/R627Q found in a 5 y.o. pt. w/epilepsy at age 5, and developed ataxia and neuropathy in his teens.		(Baruffini et al., 2011) PubMed
Liver Failure	Found in trans w/ A467T in a 1 y.o. with liver failure	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Alpers	Found in trans w/A467T in a 3 y.o. w/seizures and developmentally delayed		(Hunter et al., 2011) PubMed

Amino Acid Substitution: Q308H cDNA Position: 924 g→c (exon 4)
Disease	Genetics	Frequency	Reference
PEO	Found in trans w/W748S	Not found in 250 control individuals	(Horvath et al., 2006) PubMed

Amino Acid Substitution: R309L cDNA Position: 926 g→t (exon 4)
Disease	Genetics	Frequency	Reference
PEO	ar, Compound with T251I	Not found in 100 DNA samples	(Lamantea et al., 2002) PubMed

Amino Acid Substitution: R309H cDNA Position: 926 g→a (exon 4)
Disease	Genetics	Frequency	Reference
Alpers	Compound in trans with R627Q	Not found in 250 control individuals	(Horvath et al., 2006) PubMed
Epilepsy ataxia and developmental delay	Found in trans with G1051R in a 32 y.o. male with severe neuropathy, achalasia, epilepsy, and developmentally delayed.		(Pozzo et al., 2017) PubMed
Charcot-Marie-Tooth disease	Found as compound heterozygous in trans with G737R in a 6 year-old girl with a complex phenotype that included early onset axonal Charcot?Marie?Tooth disease (CMT).		(Phillips et al., 2019) PubMed

Amino Acid Substitution: R309C cDNA Position: 925 c→t (exon 4)
Disease	Genetics	Frequency	Reference
PEO	Found in a heterozygous 14 y.o. female patient w/ chronic intestinal pseudo-obstruction, PEO, ataxia, myopathy, and COX negative fibers	In 5 out of 80 patients w/ chronic intestinal pseudo-obstruction	(Amiot et al., 2009) PubMed
MELAS	Found in trans w/ W748C in an 18 y.o. female with seizues, vision loss, neuropathy, ophthalmoparesis. Each parent is an unaffected heterozygote.		(Ching-wan et al., 2015) PubMed
PEO, ataxia	Found as homozygous with severe peripheral neuropathy, progressive external ophthalmoplegia (PEO), ataxia, and encephalomyopathy		(Blazquez-Bermejo et al., 2019) PubMed

Amino Acid Substitution: W312R cDNA Position: 934 t→c (exon 4)
Disease	Genetics	Frequency	Reference
PEO	Found in a 39 y.o. with PEO as a heterozygous mutation	7 out of 27patients w/sporadic PEO compared to 250 controls individuals had a mutation in POLG	(Agostino et al., 2003) PubMed
Encephalopathy, dysphagia, and neuropathy	Found in trans with R574W in a 62 y.o. male	Not found in 250 control individuals	(Horvath et al., 2006) PubMed
PEO	Found as a homozygous mutation in a 58 y.o. male with dysphagia, dysphonia cataract, and mild myopathy.		(Pozzo et al., 2017) PubMed

Amino Acid Substitution: K319E cDNA Position: 955 a→g (exon 4)
Disease	Genetics	Frequency	Reference
PEO	Found in trans w/ R869Q in a 44 y.o. w/ PEO, ataxia, neuropathy, and muscle weakness	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: P324S cDNA Position: 970 t→g (exon 4)
Disease	Genetics	Frequency	Reference
Neutral polymorphism		0.6% of 450 individuals	(GeneSNPs, 2004) PubMed
	Reference # rs2307437		PubMed

Amino Acid Substitution: T326fs61X cDNA Position: 975-976 ins c stop@387 (exon 4)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans with A467T	Not found in 300 healthy French control chromosomes	(Naimi et al., 2006) PubMed
Alpers	Found in compound with A467T in a 4 yo male with mtDNA depletion	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed

Amino Acid Substitution: S332X cDNA Position: 994 del c or tc→g (exon 4)
Disease	Genetics	Frequency	Reference
	Reference # rs35954915		PubMed

Amino Acid Substitution: W347_L356 del cDNA Position: 1039-1068 del (exon 5)
Disease	Genetics	Frequency	Reference
Alpers	10 amino acid del found in trans w/A467T		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed

Amino Acid Substitution: E358A cDNA Position: 1073 a→c del364X (exon 4)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans w/A467T in a 3 y.o. w/seizures, ataxia, and developmentally delayed		(Hunter et al., 2011) PubMed

Amino Acid Substitution: E358A cDNA Position: 1073 a→c del364X (exon 4)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans w/A467T in a 4 y.o. w/seizures, ataxia, and developmentally delayed		(Hunter et al., 2011) PubMed

Amino Acid Substitution: R374X cDNA Position: 1120 c→t (STOP) (exon 5)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans w/A467T.		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed

Amino Acid Substitution: G380D cDNA Position: 1139 g→a (exon 5)
Disease	Genetics	Frequency	Reference
PEO	Sporadic mutation found in trans with A467T	Not found in 300 healthy French control chromosomes	(Naimi et al., 2006) PubMed
PEO	Found in compound with A467T in a 63 yo male with cerebellar ataxia, weakness of lower limbs and cognitive impairment	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed

Amino Acid Substitution: R386C cDNA Position: 1156 c→t (exon 5)
Disease	Genetics	Frequency	Reference
Isolated distal myopathy of upper limbs and mtDNA depletion	Found as a compound heterozygote w/ H932Y in one 27 y.o. male. Recessive inheritance of both mutated alleles confirmed.		(Giordano et al., 2010) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: R386H cDNA Position: 1157 g→a (exon 5)
Disease	Genetics	Frequency	Reference
Alpers	Heterozygous single mutation found in a 1 y.o..		(Baruffini et al., 2011) PubMed

Amino Acid Substitution: L392V cDNA Position: 1174 c→g (exon 6)
Disease	Genetics	Frequency	Reference
Neutral polymorphism	Heterozygous with muscle weakness & optic atrophy	<1 % in control populations	(Luoma et al., 2007) (Wong et al., 2008) PubMed
Alpers	Found in cis w/R1081dup and in trans w/L304R		(Cardenas et al., 2010) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: L392W cDNA Position: 1174 ct→tg (exon 6)
Disease	Genetics	Frequency	Reference
	Found in a Chinese population with Parkinsonism at an allelic frequency of 0.199	344 Chinese parkinson patients and 144 controls	(Gui et al., 2012) PubMed

Amino Acid Substitution: L411P cDNA Position: 1232y→c (exon 6)
Disease	Genetics	Frequency	Reference
Progressive ataxia and epilepsy	Found in trans w/ R574W in a 69 y.o. female with progressive gait ataxia, dysarthria, and myoclonic jerks.		( Ng et al., 2017) PubMed

Amino Acid Substitution: P412L cDNA Position: 1235 c→t (exon 6)
Disease	Genetics	Frequency	Reference
Ataxia	Found as a heterozygous mutation in a 64 y.o. female with mtDNA deletions, spastic ataxic gait, and multiple lipomas.		(Pozzo et al., 2017) PubMed

Amino Acid Substitution: R417T cDNA Position: 1250 g→c (exon 6&7 junction)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans w/A467T		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed

Amino Acid Substitution: Exon 7 deletion cDNA Position: c.1251-2 a→t (exon 6&7 splice site)
Disease	Genetics	Frequency	Reference
Alpers	Found as a compound heterozygote with A467T. The pt. was a 3.5 y.o. male with VPA induced liver toxicity.		(Schaller et al., 2011) PubMed

Amino Acid Substitution: C418R cDNA Position: 1252 t→c (exon 7)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans w/A467T.		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed
Alpers	Found in trans w/A467T in a 43 mo. old female with ataxia and seizures		(McCoy et al., 2011) PubMed

Amino Acid Substitution: L424GfsX28 cDNA Position: 1270-1271 del ct stop @ 452 (exon 7)
Disease	Genetics	Frequency	Reference
PEO	Sporadic / unknown Compound with G431V	7 out of 27patients w/sporadic PEO compared to 250 controls individuals had a mutation in POLG	(Agostino et al., 2003) PubMed
Alpers	Found in trans with A467T		(Wong et al., 2008) PubMed

Amino Acid Substitution: G426S cDNA Position: 1276 g→a (exon 7)
Disease	Genetics	Frequency	Reference
Epilepsy, ataxia, myoclonus, cataract, and cognitive delay	ar, found in a 56 yr. old pt. with 2 siblings with epilepsy	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Seizures	Found in trans w/ G737R in an 11 y.o. w/ seizures and an abnormal MRI	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: L428P cDNA Position: 1283 t→c (exon 7)
Disease	Genetics	Frequency	Reference
Alpers	Found as a heterozygote w/ A467T.	Sarzi et al. 2007 reported 2% (n=50) of patients with multiple respiratory chain deficiency with a 35% decrease of mtDNA were found with the mutation L428P. 19% (9 out of 50) had various mutations in POLG.	(Sarzi et al. 2007) PubMed

Amino Acid Substitution: M430L cDNA Position: 1288 a→t (exon 7)
Disease	Genetics	Frequency	Reference
PEO with Parkinsonism	ar, Compound (in trans) heterozygous with W918R	Absent in 200 control alleles	(Invernizzi et al., 2008) PubMed
PEO	Found in trans with W918R in a 42 y.o. male with PEO and mtDNA deletions		(Ferreira et al., 2011) PubMed

Amino Acid Substitution: G431V cDNA Position: 1292 g→t (exon 7)
Disease	Genetics	Frequency	Reference
PEO	Sporadic / unknown Compound with L424 CT deletion	7 out of 27patients w/sporadic PEO compared to 250 controls individuals had a mutation in POLG	(Agostino et al., 2003) PubMed

Amino Acid Substitution: S433C cDNA Position: 1298 c→g (exon 7)
Disease	Genetics	Frequency	Reference
PEO- ataxia, peripheral neuropathy	Found in trans with E1143G in a patient with PEO, ataxia, peripheral neuropathy, and episodes of encephalopathy. Mother had heterozygous E1143G variant, but was asymptomatic.	Hudson, 2006: Not detected in 200 controls	(Hudson et al., 2006a) PubMed
PEO	Sporadic, Found in trans with E1143G	Not found in 250 control individuals	(Horvath et al., 2006) PubMed

Amino Acid Substitution: Q449X cDNA Position: 1345 c→t (exon 7)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans w/ W748S in a 21 y.o. with seizures	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: Y452X cDNA Position: 1356 t→g (exon 7)
Disease	Genetics	Frequency	Reference
PEO	Sporadic	Not detected in 200 controls.	(Hudson et al., 2006a) PubMed
Multiple Sclerosis-like illness	Found as a heterozygous mutation w/T914A in a 56 yr. old. Pt. first diagnosed w/ optic neuritis and MS 19 yrs earlier. Currently has ragged-red muscle fibers, ptosis, myopathies, and mtDNA deletions.		(Echaniz-Laguna et al., 2010) PubMed

Amino Acid Substitution: R457Q cDNA Position: 1370 g→a (exon 7)
Disease	Genetics	Frequency	Reference
ataxia, epilepsy, neuropathy, depression, and memory loss	Found as a heterozygote in a 68 y.o. male with symptoms first noticed at age 54. Patient had numbness in both feet, tremor, epilepsy, atrial fibrillation, memory loss, ataxia, and dysarthria.		( Jerath and Shy, 2014) PubMed

Amino Acid Substitution: M459I cDNA Position: 1373 g→a (exon 7 )
Disease	Genetics	Frequency	Reference
MDS	Heterozygous in trans with G1052R.		(Puusepp et al., 2018) PubMed

Amino Acid Substitution: L463F cDNA Position: 1389 g→t (exon 7)
Disease	Genetics	Frequency	Reference
PEO	ar, Found as compound in trans with S511N	None found in 192 ethnically matched control chromosomes nor in 108 patients with PEO and 140 cases of sporadic PD	(Hudson et al., 2006b) PubMed

Amino Acid Substitution: M464T cDNA Position: 1391 t→c (exon 7)
Disease	Genetics	Frequency	Reference
neuropathy and ataxia	Found in compound with K768E in a teenage female with axonal sensorimotor neuropathy and sensory ataxia with multiple mtDNA deletions	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed

Amino Acid Substitution: A467T cDNA Position: 1399 g→a (exon 7)
Disease	Genetics	Frequency	Reference
PEO	Found as compound with L304R and R3P in PEO.  Also found as a homozygous mutation in a PEO pt.	Three out of 229 control individuals were heterozygous for A467T (allele T frequency 0.6%), while the R3P and L304R mutations were not observed.	(Van Goethem et al., 2001) PubMed
PEO	Found as compound with S1104C in a 48 y.o. pt. with PEO	7 out of 27patients w/sporadic PEO compared to 250 controls individuals had a mutation in POLG	(Agostino et al., 2003) PubMed
PEO	Found in compound with G268A	Di Fonzo 2003: Not found in 100 DNA samples from healthy Italians	(Di Fonzo et al., 2003) PubMed
PEO	Found as compound with R627Q, L304R or R3P, or G268A	Van Goethem, 2003: absent in 612 Belgian controls.	(Van Goethem et al., 2003a) PubMed
MERRF	homozygous mutation in an 18 y.o. patient w/ myoclonus, seizure, and sensory ataxic neuropathy		(Van Goethem et al., 2003b) PubMed
Alpers	Found in compound het with E873stop in Alpers w/ mtDNA depletion		(Naviaux and Nguyen, 2004) PubMed
Neurodegenerative disorders and ataxia	Found as a homozygous mutation in 2 of 8 patient w/ ataxia and neurological disorders. Also found in trans with E1143G/W748S in a 2nd patient.		(Van Goethem et al., 2004) PubMed
			(Chan et al., 2005a) PubMed
Alpers	Studied Alpers pt. fibroblasts with the compound het with E873stop w/ mtDNA depletion. Determined that transcripts containing this stop codon undergo nonsense-associated alternative splicing and nonsense-mediated decay.		(Chan et al., 2005b) PubMed
Infantile Hepatocerebral Syndrome	Found as a homozygous mutation in 1 of 9 pts. with progressive neurological and hepatic failure.  Also found as in trans w/G848S and a 3rd pt. in trans w/ A957P. Also found in trans with 3482 +2t's splice site variant in a 4th pt.	1 in 9 (11.11%) children with a combination of progressive neurological and hepatic failure, with an allelic frequency of <0.14% (0 out of 350) in the control group.	( Ferrari et al., 2005) PubMed
ataxia-myopathy syndrome	Found as a heterozygous mutation in 4 family members, and found in compound with R627Q in a 5th family member.		( Luoma et al., 2005) PubMed
Alpers	Found in trans w/ W1020X in two infants and also in trans w/ G848S in two other infants. Found as a homozygous mutation in an 8.5 y.o. male.		(Nguyen et al., 2005) PubMed
Ataxia Syndrome	Found as a homozygous mutation in 2 members of the same family with mtDNA deletions		(Winterthun et al., 2005) PubMed
PEO	Found as a homozygous mutation in a 33 y.o. male with mtDNA deletions	24 patients diagnosed with mitochondrial disease and having multiple mtDNA deletions compared to 100 controls in a Spanish population.	(Gonzalez-Vioque et al., 2006) PubMed
Encephalopathy, liver disorders, and PEO	A467T is common in children, but complete POLG1 sequencing is required to identify multiple mutations that can have complex implications for genetic counseling. Studied a large collection of patients with clinical, biochemical and molecular genetic evide	Not found in 250 control individuals	(Horvath et al., 2006) PubMed
Oxidative phosphorylation enzyme complex deficiencies	Found as a homozygous mutation in 1 of 8 patients. Also found in trans w/ R227W, R227P, W235X, G848S, and A957P.	de Vries et al. , 2007 identified 1 (4.76%) children out of 21 with a POLG mutation that were known to have a mitochondrial disorder	(de Vries et al., 2007) PubMed
Liver failure, encephalopathy, and epilepsy	Found in trans w/ R574W, G848S, W748S in children w/ progressive encephalopathy.	Not found in 200 control alleles	(Kollberg et al., 2006) PubMed
Alpers	Found in trans w/ T914P, T326fsX38, and G380D	Not found in 300 healthy French control chromosomes	(Naimi et al., 2006) PubMed
Epilepsy, PEO, and ataxia	Found as a homozygous mutation in 5 mitochondrial disease pts. Also, found in trans w/W748S in 6 pts. with mitochondrial disease.	Studied in 26 mitochondrial disease patients	(Tzoulis et al., 2006) PubMed
PEO	Identified a diverse range of phenotypes arising from PEO-associated amino acid substitutions introduced in the yeast pol gamma gene.		(Stuart et al., 2006) PubMed
Alpers	Found as a heterozygote mutation with L428P.	Sarzi et al. 2007 reported 2% (n=50) of patients with multiple respiratory chain deficiency with a 35% decrease of mtDNA were found with the mutation L428P. 19% (9 out of 50) had various mutations in POLG.	(Sarzi et al., 2007) PubMed
Alpers w/ valporate induced hepatic failure	Found in cis w/T885s and in trans w/Q879H and E1143G.		(McFarland et al., 2008) PubMed
Alpers, Ataxia Neuropathy, and arPEO+	Found in trans w/ L886P, Q68X, Q715X, T849H, T914P, L83P, G888S, R1138C, c.2480+1, c. 2157+5, G737R, and L424G		(Wong et al., 2008) PubMed
Alpers	Found in trans w/ [R852C and G11D], and, found in trans w/ T914P in 2 additional pts.  In trans w/E873X.  In trans w/ W347_L356 del.  In trans w/G848S.  In trans w/L966R.  In trans w/R374X.  In trans w/ R417T.  In trans w/C418R.  One pt., found as a homoz		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed
Alpers, PEO	Found in trans w/L605R, and in a 2nd pt. in trans w/ W748S. Also, found as a homozygous mutation.  Found in trans w/ T251I and P587L. Also found in trans w/ G11D and R852C. Also found in trans w/G848S.		(Stewart et al., 2009) PubMed
Alpers	Found in trans w/T914P		(Taanman et al., 2008) PubMed
Alpers	Found in trans w/ R574W		(Spinazzola et al., 2009) PubMed
Alpers	Homozygous		(Spinazzola et al., 2009) PubMed
Alpers	Found in trans w/ splice variant c.3643 +2t>c		(Roels, et al., 2009) PubMed
mtDNA depletion	Found in trans w/ G8484S.		(Roels, et al., 2009) PubMed
Prematurity, epilepsy, deafness, retinitis pigmentosa, hemiparesis, and liver failure	Found in trans w/ K925RfsX42	<0.5% in a Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Alpers	5 patients found with a homozygous mutation	<0.5% in a Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Epilepsy and failure to thrive	Found in trans w/ R227P	<0.5% in a Dutch population	(Blok and van den Bosch et al., 2009) PubMed
PEO, exercise intolerance, diabetes, and a 2nd pt. w/ cataract and myopathy	2 patients; found in trans w/ T251I + P587L	<0.5% in a Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Alpers	Found in trans w/S305R	<0.5% in a Dutch population	(Blok and van den Bosch et al., 2009) PubMed
PEO, ptosis, polyneuropathy, ataxia, and dysarthria	Found in trans w/ W748S and in compound w/ E1143G	<0.5% in a Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Epilepsy, myoclonus, polyneuropathy, ataxia, and cognitive delay; a 2nd pt. with epilepsy and MELAS-like symptoms	Found in trans w/ W748S	<0.5% in a Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Epilepsy, myoclonus, and developmental delay	Found in trans w/T914P	<0.5% in a Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Epilepsy, liver failure, occipital strokes, and growth retardation	Found in trans w/ A957P	<0.5% in a Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Spinocerebellar ataxia, neuro-degeneration, and impaired cognitive functions	ar, 2 patients ages 19 and 48	<0.5% in a Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Epilepsy and myoclonus	ar, found with E1143G	<0.5% in a Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Cerebellar ataxia, sensory neuropathy, PEO, and dysphagia	Found with W748S in a 43 yr. old patient		(Schulte et al., 2009) PubMed
Cerebellar ataxia, sensory neuropathy, and dysphagia	Homozygous. Found in 2 early 20 yr. old sisters, and only one with epilepsy		(Schulte et al., 2009) PubMed
SANDO	Homozygous. Found in 2 siblings in their mid 40's. mtDNA deletions and COX1 deficient fibers in muscle biopsies		(McHugh et al., 2010) PubMed
Alpers	Found in trans with G848S		(Hasselmann et al., 2009) PubMed
Hepatocerebral - Alpers symptoms	Found in trans w/P1073L in 2 pt., Psychomotor delay, seizures, liver delay, and gastrointestinal dysmotility.		(Kurt et al., 2010) PubMed
Encephalopathy	Found in trans w/ G303R in 2 brothers and a 3rd unrelated pt. All 3 had ataxia, epilepsy, and encephalopathy.	Not found in 170 control individuals	(Tzoulis et al., 2010) PubMed
SANDO	Found in trans with W748S+E1143G. Sensory ataxia, dysarthria, and opthalmoplegia.		(Posada et al., 2010) PubMed
Alpers	Found as a compound heterozygote w/ a 4.7 kb POLG deletion from intron 14 thru intron 21 w/ a CGH array. Patient had early on set of Alpers and died at the age of 3.5 y.o.. The father carried the A467T mutation, and the mother the deletion.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Compton et al., 2010 and Tang et al., 2011) PubMed
Multiple Sclerosis-like illness	Found as a heterozygous mutation w/R275Q in a 63 yr. old. Pt. first diagnosed w/ optic neuritis and MS 33 yrs earlier. Currently, pt. has ragged-red muscle fibers, ptosis, myopathies, PEO, and mtDNA deletions.		(Echaniz-Laguna et al., 2010) PubMed
Alpers	Found in trans w/ P625R in a 1 y.o. with epilepsy and liver failure.		(Baruffini et al., 2011) PubMed
Epilepsy	Found heterozygous with T 914P in a 10 mo. old male with myoclonic seizures and jerks, and developmental regression.		(Dhamija et al., 2011) PubMed
Alpers	Found in trans with E1143G, Q497H and W748S in a 6 y.o. with epilepsy and encephalopathy	7 of 136 mitochondrial disease Finnish children, and screened against 370 control DNA samples	(Isohanni et al., 2011) PubMed
Alpers	Found in trans with T914P in a 9 mo. old with epilepsy and encephalopathy	7 of 136 mitochondrial disease Finnish children, and screened against 370 control DNA samples	(Isohanni et al., 2011) PubMed
VPA induced liver toxicity	Found in trans with L304R in a 15 y.o. pt. with VPA induced hepatotoxicity	Used 968 alleles ethnically matched controls	(Stewart et al., 2010) PubMed
Alpers	Found as a compound heterozygote with the splice site mutation c.1251-2a→t resulting in the deletion of exon 7. The pt. was a 3.5 y.o. male with VPA induced liver toxicity		(Schaller et al., 2011) PubMed
Encephalopathy	Found in trans with Q715X in a 5 y.o. pt.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Liver Diseases	Compound heterozygote in cis with W748S	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ T914P in a 3 y.o. with hypotonia, encephalopathy, seizures, and developmentally delayed	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ G848S in an 8 y.o. pt. with seizures, muscle weakness, hypotonia, ataxia, hearing loss, and developmentally delayed.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ G848S in a 1 y.o. pt. with seizures and elevated transaminases, and increased signal basal ganglia	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
SANDO AND PEO	Found in trans w/ W748S in a 54 y.o. with PEO, ptosis, ataxia, neuropathy, and SANDO	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ W748S in a 16 y.o. with seizures, dystonia, choria, neuropathy, and ptosis	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Encephalopathy and ataxia	Found in trans w/ R597W in a 26 y.o. with encephalopathy, ataxis, ptosis, and neuropathy	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/K1050RfsX44 in a 4 y.o. w/ seizures, ataxia, hypotonia, and developmentally delayed.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found as a homozygote in a 46 y.o. pt. w/ ptosis, neuropathy, muscle weakness, and ataxia	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/W748S in an 18 y.o. with ataxia, seizures, dystonia, and optic atrophy.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Ataxia	Found as a homozygote in a 48 y.o. w/ hypotonia, ataxia muscle weakness, and headaches.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ c1443+1g in a 2 y.o. w/ hypotonia, encephalopathy, seizures, cardiomyopathy, and developmentally delayed.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found as a homozygote in a 19 y.o. w/ ataxia, myoclonic seizures, optic atrophy, dysarthria, and developmentally delayed.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO and seizures	Found as a homozygote in a 40 y.o. w/ PEO, ataxia, seizures, and neuropathy	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ L1113P in a 1 y.o. with encephalopathy, seizures, and hepatic failure	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ T914P in a 5 y.o. w/ seizures, hearing loss, and developmentally delayed.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Liver failure	Found in trans w/ S305R in a 1 y.o. with liver failure	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures and liver failure	Found in trans w/ R852C and G11D in a 8 mo. w/ seizures, liver failure, and lactic acidosis.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ F749S in a 6 y.o. w/ seizures	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Hepatic failure	Found in trans w/ S1095R in a 6 mo. w/ hypotonia, liver failure, abnormal muscle histology, and developmentally delayed	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ T914P in a 9 mo. w/ seizures, hypotonia, and developmentally delayed	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures and hepatic failure	Found in trans w/ T914P in a 4 y.o. with liver failure, seizures, and failure to thrive	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ Q1024X in a 2y.o. w/seizures, hearing loss, and hemiparesis	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans w/ W748S in a 29 y.o. symptoms not noted	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found in trans w/ A143V in a 49 y.o. w/ PEO, encephalopathy, ataxia, seizures, neuropathy, hearing loss, and muscle weakness	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans w/ L304R in a 15 y.o. Symptoms not noted	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Liver failure	Found in trans w/ R807C in a 1 y.o. w/ encephalopathy, liver failure, and lactic acidosis	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ T914P in an 8 mo. w/ seizures, respiratory failure, and an abnormal MRI	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans w/ F749S in an 8 mo. symptoms not noted	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures and hepatic failure	Found in trans w/ H754Q in a 2 y.o. w/ seizures, hepatic failure, and cerebellar atrophy.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ C1188R in a 3 y.o. w/ seizures, hypotonia, and developmentally delayed	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
VPA induced liver failure	Found in trans w/ G588D in a 2 y.o. w/ VPA induced liver failure	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans w/ F88L in a 42 y.o. w/ no symptoms noted	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Alpers	Found in trans w/G848S in a 3 y.o. w/seizures, developmentally delayed, and ataxia		(Hunter et al., 2011) PubMed
Alpers	Found in trans w/G848S in a 11 mo. old w/seizures and developmentally delayed		(Hunter et al., 2011) PubMed
Alpers	Found as a homozygous mutation in a 10 y.o. w/seizures and developmentally delayed		(Hunter et al., 2011) PubMed
Alpers	Found in trans w/IVS14+1G>A in a 2 y.o. w/seizures, developmentally delayed, and ataxia		(Hunter et al., 2011) PubMed
Alpers	Found in trans w/R852C in a 5 y.o. w/seizures, ataxia, and developmentally delayed		(Hunter et al., 2011) PubMed
Alpers	Found in trans w/S305R in a 3 y.o. w/seizures and developmentally delayed		(Hunter et al., 2011) PubMed
Alpers	Found in trans w/L966R in a 1 y.o. w/ seizures and developmentally delayed		(Hunter et al., 2011) PubMed
Alpers	Found in trans w/E358A del364X in a 3 y.o. w/seizures, ataxia, and developmentally delayed		(Hunter et al., 2011) PubMed
Alpers	Found in trans w/E358A del364X in a 4 y.o. w/seizures, ataxia, and developmentally delayed		(Hunter et al., 2011) PubMed
Alpers	Found in trans w/L966R in a 1 y.o. w/ seizures and developmentally delayed		(Hunter et al., 2011) PubMed
Infantile hepatocerebral	Found in trans w/R232H and H277L in a 2 mo. old w/hypotonia, motor paresis and developmentally delayed		(Hunter et al., 2011) PubMed
Infantile hepatocerebral	Found in trans w/R232H and H277L in a 1.5 mo. old w/hypotonia and developmentally delayed		(Hunter et al., 2011) PubMed
Alpers	Found in trans w/ R574W in 2 pediatric patients w/mitochondrial encephalomyopathy, seizures, ataxia, and ophthalmological involvement		(Sofou et al., 2012) PubMed
Alpers	Found in trans w/ G848S in a pediatric patient w/mitochondrial encephalomyopathy, seizures, ataxia, and ophthalmological involvement		(Sofou et al., 2012) PubMed
Alpers	Found in trans w/ G303R in a pediatric patient w/mitochondrial encephalomyopathy, seizures, ataxia, and ophthalmological involvement		(Sofou et al., 2012) PubMed
Alpers	Found in trans w/L966R in a 17 mo. old male with seizures and encephalopathy		(McCoy et al., 2011) PubMed
Alpers	Found in trans w/G848S in a 10 mo. old female with seizures and brain stem dysfunction. History revealed that a 24 y.o. cousin died from Alpers whom harbored a homozygous A467T variant.		(McCoy et al., 2011) PubMed
Alpers	Found in trans w/R852C in a 21 mo. old female with blindness, anarthria, hypotonia, and epilepsy		(McCoy et al., 2011) PubMed
Alpers	Found in trans w/C418R in a 43 mo. old female with ataxia and seizures		(McCoy et al., 2011) PubMed
Alpers to Leigh's encephalopathy	Found in trans w/G848S in a 3.5 mo. old female with seizures and Alpers. Post mortem studies revealed Leigh's encephalopathy		(Scalais et al., 2012) PubMed
MNGIE-like	Found as a homozygous mutation in a 46 y.o. male with PEO, ptosis, exercise intolerance, peripheral neuropathy, ataxia, and hearing loss		(Tang et al., 2012) PubMed
Torticollis and PEO	Found in trans w/W748S in a 43 y.o. female with abnormal gait, ataxia, PEO, and head jerks.		(Tuladhar et al., 2012) PubMed
Parieto-occipital lobe epilepsy	Found in trans w/ W748S in a 16 y.o. female with seizures, headaches, cerebellar ataxia, axonal neuropathy, visual impairment, and impaired cognitive function		(Roshal et al., 2011) PubMed
PEO	Found in trans w/W748S in a 24 y.o. female with arPEO, cerebellar ataxia, and mtDNA deletions		(Lax et al., 2012b) PubMed
PEO	Found in trans w/X1240Q in a 59 y.o. male with arPEO and sensory neuropathy		(Lax et al., 2012b) PubMed
PEO	Found in trans w/X1240Q in a 59 y.o. male with arPEO, ptosis and sensory neuropathy		(Lax et al., 2012a) PubMed
PEO	Found in trans w/X1240Y in a 42 y.o. Female with arPEO, ptosis and sensory neuropathy		(Lax et al., 2012a) PubMed
PEO	Found as a homozygous mutation in a 36 y.o. male with arPEO, ptosis and sensory neuropathy		(Lax et al., 2012a) PubMed
PEO	Found in trans w/W748S in a 47 y.o. male with arPEO, ptosis and sensory neuropathy		(Lax et al., 2012a) PubMed
PEO	Found in trans w/X1240Y in a 42 y.o. female with PEO, ptosis and sensory neuropathy		(Lax et al., 2012a) PubMed
PEO	Found as a homozygous mutation in a 44 y.o. male with arPEO, ptosis and sensory neuropathy		(Lax et al., 2012a) PubMed
PEO	Found in trans w/W748S in a 48 y.o. male with PEO, ptosis, ataxia and sensory neuropathy		(Lax et al., 2012a) PubMed
Epilepsy	Found in trans w/W748S in a 18 y.o. female with epilepsy, ataxia and sensory neuropathy		(Lax et al., 2012a) PubMed
Epilepsy	Found in trans w/W748S in a 20 y.o.female with epilepsy, ataxia and sensory neuropathy		(Lax et al., 2012a) PubMed
	Found in a Chinese population with Parkinsonism at an allelic frequency of 0.028	344 Chinese parkinson patients and 144 controls	(Gui et al., 2012) PubMed
PEO	Found in compound with G380D in a 63 yo male with cerebellar ataxia, weakness of lower limbs and cognitive impairment	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
Alpers	Found in compound with T326fs61X in a 4 yo male with mtDNA depletion	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
Alpers	Found in compound withT914P in a 15 month female with mtDNA depletion	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
Epilepsy	Found in compound withW748S in a 17 yo female with axonal neuropathy, cerebellar ataxia, and hyperintensity of rolandic,	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
Sensorimotor neuropathy	Found as a heterozygous mutation in a 60 yo with ALS-like symptoms and mtDNA deletions.	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
Encephalopathy	Found as a homozygous mutation in 2 teens both had epilepsy, ataxia, and PEO		(Tzoulis et al., 2013) PubMed
Encephalopathy	Found as a heterozygous mutation with W748S in 2 patients with PEO and ataxia.		(Tzoulis et al., 2013) PubMed
Encephalopathy	Found as a heterozygous mutation with G848S in a patient with epilepsy		(Tzoulis et al., 2013) PubMed
SANDO	Found in trans with T251I and P587L in a female in her 60's with a 5 year history of peripheral neuropathy, blurred vision, unstable gait, and sensory ataxia, dementia, and ophthalmoplegia.		(Lovan et al., 2013) PubMed
Epilepsy	Found with S1104F in a 5 y.o. male. Patient also had myopathy and ataxia. In a study using patient fibroblasts, the cells were unable to up regulate mitochondrial biogenesis when exposed to Valproic acid.		(Sitarz et al., 2014) PubMed
MIRAS	Found with W748S in a 39 y.o. male. Patient also had Ataxia, PEO, and neuropathy. In a study using patient fibroblasts, the cells were unable to up regulate mitochondrial biogenesis when exposed to Valproic acid.		(Sitarz et al., 2014) PubMed
Alpers	Found in a 1 y.o female with c.3626_3629dupGATA, located 14nt before the end of exon 22 resulting in the in a premature stop codon and the skipping of most of exon 22.		(de Camaret et al., 2014) PubMed
SANDO	Found w/W748S in a 37 y.o. female with ataxia, ptosis, seizures, and mtDNA deletions.		(Hanisch et al., 2014) PubMed
SANDO	Found as a homozygous mutation in a 40 y.o. male with ataxia ptosis, and mtDNA deletions.		(Hanisch et al., 2014) PubMed
SANDO	Found w/W748S in a 56 y.o. male with ataxia, ptosis, diabetes and mtDNA deletions.		(Hanisch et al., 2014) PubMed
SANDO	Found w/W748S in a 45 y.o. male with ataxia, ptosis, diabetes and mtDNA deletions.		(Hanisch et al., 2014) PubMed
SANDO	Found w/R627Q in a 50 y.o. male with ataxia, ptosis, diabetes and mtDNA deletions.		(Hanisch et al., 2014) PubMed
Myocerebrohepatopathy	Found w/S1095R in a 4 y.o. boy with hypotonia, failure to thrive, and abnormalities in cranial nerve enhancement		(Horst et al., 2014) PubMed
PEO and encephalopathy	Found as a homozygous mutation in a 15 y.o. w/epilepsy, ataxia, and neuropathy		(Tzoulis et al., 2014) PubMed
PEO and encephalopathy	Found as a homozygous mutation in a 8 y.o. w/epilepsy, ataxia, and neuropathy		(Tzoulis et al., 2014) PubMed
PEO and encephalopathy	Found as a homozygous mutation in a 16 y.o. w/epilepsy, ataxia, and neuropathy		(Tzoulis et al., 2014) PubMed
Encephalopathy	Found w/W748S in a 14 y.o. w/epilepsy, ataxia, and neuropathy		(Tzoulis et al., 2014) PubMed
Encephalopathy	Found w/W748S in a 13 y.o. w/epilepsy, ataxia, and neuropathy		(Tzoulis et al., 2014) PubMed
Encephalopathy	Found w/G303R in a 9 mo. child w/epilepsy and death at 1.1 yrs.		(Tzoulis et al., 2014) PubMed
Encephalopathy	Found w/G303R in a 2 y.o child w/epilepsy, ataxia, and death at 8.0 yrs.		(Tzoulis et al., 2014) PubMed
Encephalopathy	Found w/G848S in a 6 mo. child w/epilepsy and death at 6 mo.		(Tzoulis et al., 2014) PubMed
PEO	Found in compound w/ M919T in a 23 y.o. female patient w/ chronic intestinal pseudo-obstruction, PEO, and ataxia.	In 5 out of 80 patients w/ chronic intestinal pseudo-obstruction	(Amiot et al., 2009) PubMed
Alpers	Found as a homozygous mutation in a 3 y.o. female with seizures, cortical degeneration, hepatic microsteatosis,hippocampal sclerosis, and mtDNA depletion and multiple mtDNA mutations.	Carrier frequency in European ancestry of 0.2% to 0.3%	(Rajakulendran et al., 2016) PubMed
MEMSA	Found as a homozygous mutation in a 6 y.o. female with encephalitis, occipital lesions, COX-negative muscle fibers and mtDNA deletions and multiple mtDNA mutations.	Carrier frequency in European ancestry of 0.2% to 0.3%	(Rajakulendran et al., 2016) PubMed
SANDO	Found as a homozygous mutation in a 20 y.o. male with diplopia, axonal neuropathy, ragged red fibers, COX-negative muscle fibers, mtDNA deletions and multiple mtDNA mutations.	Carrier frequency in European ancestry of 0.2% to 0.3%	(Rajakulendran et al., 2016) PubMed
MELAS-like	Found as a homozygous mutation in a 24 y.o. female with axonal sensory motor neuropathy, ragged red fibers, COX-negative muscle fibers, mtDNA deletions and multiple mtDNA mutations.	Carrier frequency in European ancestry of 0.2% to 0.3%	(Rajakulendran et al., 2016) PubMed
Migrains, siezures, and ataxia	Found as a compound heterozygote w/ W748S in a 22 y.o. female with epileptic siezures, migrains and ataxia. Her brother presented with siezures at 19 yrs. w/ same mutations.		(Vinjam et al., 2015) PubMed
	A study of 68 patients w/ homozygous A467T. Concluded that the clinical presentation was highly variabl, butthat siblings had similar clinical presentations. Attributed the variablitiy to genetic, enviromental, and epigentic factors.		(Neeve et al., 2012) PubMed
MSCA	Found in trans withW748S in a 24 y.o.with encephalopathy, ataxia, and myopathy. In a study that suggests that dopaminergic neurons are vulnerable to the accumulation of somatic mtDNA damage, and defects of mtDNA replication and repair.		(Tzoulis et al., 2016) PubMed
MSCA	Found in trans with W748ST in a 36 y.o.with encephalopathy, ataxia, and myopathy. In a study that suggests that dopaminergic neurons are vulnerable to the accumulation of somatic mtDNA damage, and defects of mtDNA replication and repair.		(Tzoulis et al., 2016) PubMed
MSCA	Found in trans with W748ST in a 40 y.o.with encephalopathy, ataxia, and myopathy. In a study that suggests that dopaminergic neurons are vulnerable to the accumulation of somatic mtDNA damage, and defects of mtDNA replication and repair.		(Tzoulis et al., 2016) PubMed
MSCAE	Found in trans with W748S in a16 y.o.with encephalopathy, epilepsy, myopathy, and ataxia. In a study that suggests that dopaminergic neurons are vulnerable to the accumulation of somatic mtDNA damage, and defects of mtDNA replication and repair.		(Tzoulis et al., 2016) PubMed
MSCAE	Found as a homozygous mutation in a 15 y.o.with encephalopathy, epilepsy, SLE, and ataxia. In a study that suggests that dopaminergic neurons are vulnerable to the accumulation of somatic mtDNA damage, and defects of mtDNA replication and repair.		(Tzoulis et al., 2016) PubMed
Alpers	Found as a homozygous mutation in a 3 y.o. girl who had delayed development and epilepsy.		(Rajakulendran et al., 2016) PubMed
MEMSA	Found as a homozygous mutation in a 6 y.o. female with sensory axonal peripheral neuropathy, vision impairment,myoclonus, and COX negative fibers.		(Rajakulendran et al., 2016) PubMed
SANDO	Found as a homozygous mutation in a 20 y.o. male with diplopia,bilateral ptosis, and sensory peripheral neuropathy.		(Rajakulendran et al., 2016) PubMed
"MELAS-like"	Found as a homozygous mutation in a 24 y.o. female with seizure, .deafness, axonal neuropathy, and myopathic weakness.		(Rajakulendran et al., 2016) PubMed
SANDO	Found in trans w/W748S with PEO, deafness, migraines, and depression.		(Bereau et al., 2016) PubMed
SCAE	Found a homozygous mutation with ataxia, seizures, polyneuropathy, and migraine.		(Bereau et al., 2016) PubMed
SANDO	Found in trans w/R597W in a 20 y.o. with ataxia, polyneuropathy, ophthalmoparesis, and dysarthria,		(Bereau et al., 2016) PubMed
PEO	Found in trans with T251I and W748S in a 30 y.o. with muscle weaknes and PEO.		(Bereau et al., 2016) PubMed
SANDO	Found in trans with R1138C in a 35 y.o. with PEO, ataxia, sensory neuropathy, muscle weakness, and Chorea.		(Bereau et al., 2016) PubMed
SCAE	Found in trans with W748S and E1143G in a 36 y.o. with PEO, ataxia, sensory neuropathy, seizures, and migraines.		(Bereau et al., 2016) PubMed
SANDO	Found in trans with L559P in a 50 y.o. with PEO, ataxia, sensory neuropathy, dysarthria, dysphagia, and muscle weakness.		(Bereau et al., 2016) PubMed
PEO	Found in trans w/T251 and P587L in a 56 y.o. with PEO, muscle weakness, and dysphagia.		(Bereau et al., 2016) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in trans w/T251I and P587L in a 58 y.o. with ataxia, sensory neuropathy, and dysphagia.		(Bereau et al., 2016) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in trans w/R275Q in a 62 y.o. with ataxia, sensory neuropathy and PEO.		(Bereau et al., 2016) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in trans w/T251I and P587L in a 66 y.o. with ataxia, sensory neuropathy, and PEO.		(Bereau et al., 2016) PubMed
SANDO	Found in trans w/G848S with ataxia, sensory neuropathy, dysarthria, and PEO.		(Bereau et al., 2016) PubMed
Gait disturbance	Found w/ W748S in a 26 y.o. female with ataxia, speech abnormalities, and swallowing abnormalities		(Vogel et al., 2017) PubMed
Gait disturbance	Found w/ W748S in a 36 y.o. female with ataxia, speech abnormalities, and swallowing abnormalities		(Vogel et al., 2017) PubMed
Gait disturbance	Found as a heterozygote in a 27 y.o. male with ataxia, speech abnormalities, and swallowing abnormalities		(Vogel et al., 2017) PubMed
Gait disturbance	Found as a heterozygote in a 12 y.o. female with ataxia, speech abnormalities, and swallowing abnormalities		(Vogel et al., 2017) PubMed
Gait disturbance	Found w/W748S in a 49 y.o. female with ataxia, speech abnormalities, and swallowing abnormalities		(Vogel et al., 2017) PubMed
Hypoacusis	Found as a heterozygote in a 20 y.o. male with ataxia, speech abnormalities, and swallowing abnormalities		(Vogel et al., 2017) PubMed
Gait disturbance	Found w/W748S in a 41 y.o. female with ataxia, speech abnormalities, and swallowing abnormalities		(Vogel et al., 2017) PubMed
SANDO	Found in trans w/W748S in a 50 y.o female with multisystem degeneration and cerebellar ataxia. Patient was symptomatic in her 20's which progressed to SANDO. Patient died of sudden cardiac arrest at the age of 50.		(Kirschenbaum et al., 2017) PubMed
Alpers	Found in trans with G848S in two babies		(Hayhurst et al., 2019) PubMed
Seizure, VPA induced liver failure	Found as homozygous in a 20 y.o. male with seizures and VPA induced liver failure.Survived after liver transplantation.		(Bassett et al., 2019) PubMed
MDS	Found in a large cohort study as homozygous or heterzygous in trans with W748S.	Homozygous variant 7% in early onset, 13% Juvenile/adult onset, 5% late onset. Heterzygous variants in trans with W748S 6% in early onset, 23% Juvenile/adult onset, 5% late onset.	(Hikmat et al., 2020) PubMed
MTDPSA4	Found as compound heterozygous in trans with Y282D in a girl who died at the age of 4 years because of MTDPSA4.		(Pauly et al., 2019) PubMed

Amino Acid Substitution: N468D cDNA Position: 1402 a→g (exon 7)
Disease	Genetics	Frequency	Reference
PEO	Found in trans w/A1105T in 3 family members w/ PEO		(Wanrooij et al., 2004) PubMed
Microcephaly, cerebellar atrophy, hypotonia, and retinitis pigmentosa	Found as a heterozygous mutation in a 15 y.o. female w/ progressive cerebellar atrophy, hypotonia, and retinitis pigmentosa.	<0.5% in a Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Sensory neuropathy and PEO	Heterozygous. Found in 3 related patients. A father with PEO, and a son with cerebellar ataxia and dysphagia, and the father's sister with PEO only		(Schulte et al., 2009) PubMed
Opthmalplegia and peripheral neuropathy	Found in trans w/T851A in a 49 y.o. female with ptosis, lower limb weakness, sensory ataxia, gastrointestinal symptoms, and peripheral neuropathy	1 in 322 mitochondrial disease patients	(Woodbridge et al., 2012) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: c. 1433 +1g→a cDNA Position: 1433 ins g→a (Splice variant between ex 7 and ex 8)
Disease	Genetics	Frequency	Reference
Seizures	Found in trans w/ A467T in a 2 y.o. w/ hypotonia, encephalopathy, seizures, cardiomyopathy, and developmentally delayed.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: Y479X cDNA Position: 1433 large del (exon 8)
Disease	Genetics	Frequency	Reference
	Reference # rs71653298		PubMed

Amino Acid Substitution: W486X cDNA Position: 1458 g→a (exon 8)
Disease	Genetics	Frequency	Reference
Parkinsonism and PEO	Found in trans w/P587L and T251I. Found in a 68 y.o. female w/ exercise intolerance, PEO, facial diparesis, and left-dominant postural tremor.		(Miguel, et al., 2014) PubMed

Amino Acid Substitution: Q497H cDNA Position: 1491 g→c (exon 8)
Disease	Genetics	Frequency	Reference
Ataxia Syndrome	Found allelic (cis) with W748S + E1143G	1 in 97 found in healthy controls and 1 in 99 found mtDNA disease patients	(Winterthun et al., 2005) PubMed
Alpers, Ataxia Neuropathy	In cis with W748S-E1143G. Also found in trans w/G848S, and also in trans w/A467T.		(Wong et al., 2008) PubMed
Alpers	In cis w/ W748S and E1143G, and in trans w/ G848S.	Found in one child w/ a normal brain MRI	(Brunetti-Pierri et al., 2008) PubMed
Alpers	Found in cis with E1143G and W748S, and in trans with A467T in a 6 y.o. with epilepsy and encephalopathy	7 of 136 mitochondrial disease Finnish children, and screened against 370 control DNA samples	(Isohanni et al., 2011) PubMed
Charcot-Marie Tooth Disease	Found w/W748S in a Norweign family with Charcot-Marie Tooth Disease.	Total of 245 affected persons from 116 Charcot-Marie tooth disease families in Akershus County Norway.	(Hoyer et al., 2014) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: K498T cDNA Position: 1493 a→c (exon 8)
Disease	Genetics	Frequency	Reference
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: S511N cDNA Position: 1532 g→a (exon 8)
Disease	Genetics	Frequency	Reference
PEO	ad	None found in 192 ethnically matched control chromosomes nor in 108 patients with PEO and 140 cases of sporadic PD	(Hudson et al., 2006b) PubMed

Amino Acid Substitution: K512M cDNA Position: 1535 a→t (exon 8)
Disease	Genetics	Frequency	Reference
Parkinsonism	Found as a heterozygous mutation in a 79 yo male with PEO and parkinsonism		(Dulhon et al., 2013) PubMed

Amino Acid Substitution: G517V cDNA Position: 1550 g→t (exon 8)
Disease	Genetics	Frequency	Reference
Ataxia - neuropathy	Found in trans w/ E1143G in a father and his 8 y.o. daughter w/ exercise intolerance, ataxia, and neuropathy.	Not found in 250 control individuals	(Horvath et al., 2006) PubMed
Leigh Syndrome	Found as a heterozygous mutation in a female pt. w/ dominant ataxia and neuropathy	Sarzi et al. 2007 reported 2% (n=50) of patients with multiple respiratory chain deficiency with a 35% decrease of mtDNA were found with the mutation L428P. 19% (9 out of 50) had various mutations in POLG.	(Sarzi et al., 2007) PubMed
Myopathy and micro-cephaly	Found in trans w/ D1196N and R1128H		(Wong et al., 2008) PubMed
adPEO	Heterozygous, short-stature, Leigh-like disease, neuropathy, stroke, dystonia, chorea, diabetes, myoclonus, Sideroblastic anemia, splenomegaly, Pearson Syndrome to KSS		(Wong et al., 2008) PubMed
Myoclonic epilepsy	In trans w/R722H, and in association w/ a mutation in SCN1A, R1645Q		(Bolszak et al., 2009) PubMed
Cerebellar ataxia, dystonia, epilepsy, PEO, hypotonia, mental retardation, and chorea	ad, 4 patients ages 4-40 yrs.	<0.5% in a Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Seizures, hypoglycemia, myoclonus, hypotonia, and developmental delay	Heterozygous, found in 2 half siblings and their unaffected mother		(Burusnukul and de los Reyes, 2009) PubMed
Cerebellar ataxia, PEO, and dysphagia	Heterozygous. Found in a 44 yr. old patient		(Schulte et al., 2009) PubMed
Diabetes, strokes, psychosis, and epilepsy	Heterozygous. Ad, found in twins, their mother, and grandmother		(Hopkins et al., 2009) PubMed
PEO	56 y.o. male with a heterozygous mutation, and ptosis, myopathy, neuropathy, and mtDNA deletions.		(Ferreira et al., 2011) PubMed
PEO	Found as a heterozygous mutation in a 33 y.o. female with PEO and mtDNA deletions. Father also affected.		(Ferreira et al., 2011) PubMed
PEO	Found in cis w/ Y955C in a 47 y.o. w/ PEO, ptosis, myopathy, and neuropathy	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures and mitochondrial myopathy	Found as a heterozygous mutation in a 56 y.o. woman with mitochondrial myopathy, seizures, ataxia, dysarthria, and dysphonia	1 in 322 mitochondrial disease patients	(Woodbridge et al., 2012) PubMed
Neuronal ceroid lipofuscinosis	Maternally inherited heterozygous mutation found with a mutation in CLN5. Infant with hypotonia, bilateral ptosis, and diffuse cerebral atrophy. A 45% reduction in mtDNA compared to controls.		(Staropoli et al., 2012) PubMed
Neutral polymorphism	Biochmeical analysis of the recombinant Pol gamma with G517V revealed wild type activity		(Kasiviswanathan and Copeland, 2011) PubMed
Parkinsonism	Found in a male 42 y.o. male with a RAB39B variant. Has L- DOPA response, spastic paraparesis, cerebellar dysfunction, and early Parkinsonism.	1of 344 Parkinson patients	(M. Guldner, el al. 2016) PubMed
PEO	Found in trans w/Q1236H in a 23 y.o. with PEO and hypostenia.		(Pozzo et al., 2017) PubMed

Amino Acid Substitution: R546C cDNA Position: 1636 c→t (exon 9)
Disease	Genetics	Frequency	Reference
Neutral polymorphism		1.1% of 450 individuals	(GeneSNPs, 2004) PubMed
	Heterozygous with R628Q in one breast tumor		(Singh et al, 2009) PubMed
	Reference # rs2307447		PubMed

Amino Acid Substitution: R546S cDNA Position: 1636 c→a (exon 9)
Disease	Genetics	Frequency	Reference
	Reference # rs2307447		PubMed

Amino Acid Substitution: R546G cDNA Position: 1636 c→g (exon 9)
Disease	Genetics	Frequency	Reference
	Reference # rs2307447		PubMed

Amino Acid Substitution: L559P cDNA Position: 1676 t→c (exon 9)
Disease	Genetics	Frequency	Reference
SANDO	Found in trans with L559P in a 50 y.o. with PEO, ataxia, sensory neuropathy, dysarthria, dysphagia, and muscle weakness.		(Bereau et al., 2016) PubMed

Amino Acid Substitution: K561M cDNA Position: 1882 a→t (exon 9)
Disease	Genetics	Frequency	Reference
Dysmorphy, hypotonia, coloboma, heart failure, and liver insufficiency	Compound heterozygosity in cis with W748S	Sarzi et al. 2007 reported 2% (n=50) of patients with multiple respiratory chain deficiency with a 35% decrease of mtDNA were found with the mutation K561M in cis with W748S.	(Sarzi et al., 2007) PubMed

Amino Acid Substitution: R562Q cDNA Position: 1685 g→a (exon 9)
Disease	Genetics	Frequency	Reference
PEO	sporadic	Not found in 100 DNA samples from healthy Italians	(Di Fonzo et al., 2003) PubMed

Amino Acid Substitution: H569Q cDNA Position: 1707 c→(a or g) (exon 9)
Disease	Genetics	Frequency	Reference
Hepatocerebral	Homozygous		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed

Amino Acid Substitution: c. 1713-21 T>A cDNA Position: 1713 -21 (exon 10)
Disease	Genetics	Frequency	Reference
PEO	Found in trans w/L304R in a 23 y.o.with PEO, ataxia, and myopathy. In a study that suggests that dopaminergic neurons are vulnerable to the accumulation of somatic mtDNA damage, and defects of mtDNA replication and repair.		(Tzoulis et al., 2016) PubMed

Amino Acid Substitution: R574W cDNA Position: 1720 c→t (exon 10)
Disease	Genetics	Frequency	Reference
PEO	Found in trans w/ W312R in a 37 y.o. male patient w/ PEO, dysphagia, and myopathy.	Not found in 250 control individuals	(Horvath et al., 2006) PubMed
Liver failure, encephalopathy, and epilepsy	Found in trans w/A467T in 2 family members whose parent are unaffected heterozygotes.	Kollberg, 2006: Not found in 200 control alleles	(Kollberg et al., 2006) PubMed
Alpers	Found in trans w/ A467T		(Spinazzola et al., 2009) PubMed
Alpers	Found in trans w/ A467T in 2 pediatric patients w/mitochondrial encephalomyopathy, seizures, ataxia, and ophthalmological involvement		(Sofou et al., 2012) PubMed
Progressive ataxia and epilepsy	Found in trans w/ L411P in a 69 y.o. female with progressive gait ataxia, dysarthria, and myoclonic jerks.		( Ng et al., 2017) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: R579W cDNA Position: 1735 c→t (exon 10)
Disease	Genetics	Frequency	Reference
PEO	Sporadic / unknown Compound with A889T	Not detected in 120 healthy control alleles	(Filosto et al., 2003) PubMed

Amino Acid Substitution: W585X cDNA Position: 1754 g→a (exon 10)
Disease	Genetics	Frequency	Reference
PEO	Found in trans with P648R in a 50 y.o. male with PEO, dysphagia, dysphonia, and parkinsonism with mtDNA deletions		(Ferreira et al., 2011) PubMed

Amino Acid Substitution: P587L cDNA Position: 1760 c→t (exon 10)
Disease	Genetics	Frequency	Reference
PEO, neuropathy, and hearing loss	Found in trans w/ Q1236H in 2 different families and affected siblings	Filosto, 2003: not detected in 120 healthy control alleles.	(Filosto et al., 2003)  PubMed
PEO and mtDNA deletions	Found in compound w/T251I/ R807P in1 pt. and w/T251I/ H932Y in a 2nd pt. A 3rd pt. was found in compound w/T251 only. The study includes 31 mitochondrial myopathy patients w/ mtDNA deletions.	Di Fonzo 2003: Not found in 100 DNA samples from healthy Italians.	(Di Fonzo et al., 2003) PubMed
PEO	Found in compound w/T251I and N864S in 2 sisters.	Van Goethem, 2003: Not found in 280 control chromosomes.	(Van Goethem et al., 2003c) PubMed
Infantile Hepatocerebral Syndrome	Found in compound w/T251I and R232G	Ferrari et al., 2005 reported 1 in 9 (11.11%) children with a combination of progressive neurological and hepatic failure, with a heterozygous frequency of 1% of Italian controls.	(Ferrari et al., 2005) PubMed
PEO	Found in compound w/T251I and G8484S in a 75 y.o. male		(Kollberg et al., 2005) PubMed
PEO	Found as compound in trans w/ S1176L, G848S, G785X, V1106I, R309L and R227W and cis w/ T251I.  Also, T251I/P587L was found as a homozygous mutation.		(Lamantea and Zeviani, 2004)  PubMed
PEO	Found in cis w/T251I and trans w/M603L. Also found in trans w/ R853W (no T251I). All had mtDNA deletions.	24 patients diagnosed with mitochondrial disease and having multiple mtDNA deletions compared to 100 controls in a Spanish population.	(Gonzalez-Vioque et al., 2006) PubMed
Alpers	Found in cis w/ T251I and in trans w/ G848S, also found as a hetero. mutation with ataxia, ptosis, and neuropathy		(Wong et al., 2008) PubMed
Alpers	Found in trans w/R232G and in cis w/T251I. Also, in cis w/P589L and in trans w/W748S.		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed
Alpers	Found in cis with T251I with both mutations on each allele. Also, found in cis w/A467T and in trans w/T251I.		(Stewart et al., 2009) PubMed
mtDNA depletion	In cis w/T251I and in trans w/E1136K		(Taanman et al., 2008) PubMed
Hepatocerebral MDS	Found in cis w/ T251I and in trans w/ R232G		(Spinazzola et al., 2009) PubMed
Restless leg syndrome, ptosis, diplopia, limb weakness, blurred vision	Found in trans with T251I.		(Aitken, et al., 2009) PubMed
PEO	Found in cis with W748S and in trans with T251I.		(Tzoulis, et al., 2009) PubMed
PEO and mental retardation	Found in cis w/ T251I and in trans w/ R275X	>0.5% of Dutch population	(Blok and van den Bosch et al., 2009) PubMed
PEO, exercise intolerance, diabetes and a 2nd pt. w/ cataract and myopathy	Found in cis w/T251I and in trans w/A467T	>0.5% of Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Ptosis	Found in cis w/T251I and in trans w/G848S	>0.5% of Dutch population	(Blok and van den Bosch et al., 2009) PubMed
PEO, ptosis, epilepsy, mental retardation, ataxia, polyneuropathy, and cataract	Ad, in cis w/T251I 3 patients: 4 yr. old w/PEO, ptosis, and motor delay development. A 10 yr. old with epilepsy and mental retardation, and 44 yr. old w/ cataract, polyneuropathy, myopathy, and ataxia	>0.5% of Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Seizures, hypotonia, and developmental delay	Found w/T251I		(Burusnukul and de los Reyes, 2009) PubMed
Acute disseminated encephalomyelitis	Found w/T251I, found in one 4 yr. old patient with autoimmune central nervous system disease		(Harris et al., 2010) PubMed
SANDO	Found sporadically w/T251I and G848S in a 80 yr. old male		(Weiss and Saneto, 2010) PubMed
Ptosis and myopathy	Found in cis with T251I and in trans with P648R in a 59 y.o. male with dysphagia, dysphonia, myopathy, ptosis, and mtDNA deletions. Father had same symptoms.		(Ferreira et al., 2011) PubMed
PEO	Found in cis w/ T251I and in trans w/ H932Y in a 31 y.o. w/ neuropathy, PEO, ptosis, and COX deficiency.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Peripheral Neuropathy	Found in cis w/ T251I and in trans w/ H932Y in a 40 y.o. w/ peripheral neuropathy, ptosis, and muscle weakness.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found in cis w/ T251I and in trans w/ G848S in an 80 y.o. w/ peripheral neuropathy, ptosis, and abnormal muscle histology.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found in cis w/ T251I and in trans w/ K1191N in a 39 y.o. w/ PEO, neuropathy, ptosis, and muscle weakness	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in cis w/ T251I and in trans w/ N1157S in a 9 y.o. Symptoms not noted	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans w/ G588D and in cis w/ T251I in a 6 y.o. w/ no symptoms noted	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
SANDO	Found in cis with T251I and in trans with A467T in a female in her 60's with a 5 year history of peripheral neuropathy, blurred vision, unstable gait, and sensory ataxia, dementia, and ophthalmoplegia.		(Lovan et al., 2013) PubMed
SANDO	Found in cis w/T251I and in trans w/R869Q in a 34 y.o. female with ataxia, ptosis, diabetes and mtDNA deletions.		(Hanisch et al., 2014) PubMed
PEO	Found in compound w/T251I and D1184N in a 33 y.o. female patient w/ chronic intestinal pseudo-obstruction, PEO, and ataxia.	In 5 out of 80 patients w/ chronic intestinal pseudo-obstruction	(Amiot et al., 2009) PubMed
PEO	Found in compound w/T251I and D1184N in a 30 y.o. male patient w/ chronic intestinal pseudo-obstruction and PEO.	In 5 out of 80 patients w/ chronic intestinal pseudo-obstruction	(Amiot et al., 2009) PubMed
	Found in compound w/ P116Q and T251I in an Italian 8 y.o. female with fatigue,hypotonia, and delayed psychomotor development with no mtDNA depletion. Diabetic father was positive for P116Q and the deaf mother was positive for T251I and P587L.	0 found in 200 chromosome controls	(Scuderi, et al., 2015) PubMed
	Found in compound w/ P116QI and T251I in an Italian 14 y.o. male with fatigue,hypotonia, left eye ptosis, migrains, but normal cognitive skills. Diabetic father was positive for P116Q and the deaf mother was positive for T251I and P587L.	0 found in 200 chromosome controls	(Scuderi, et al., 2015) PubMed
Parkinsonism and PEO	Found in cis w/T251I and in trans w/W468X. Found in a 68 y.o. female w/ exercise intolerance, PEO, facial diparesis, and left-dominant postural tremor.		(Miguel, et al., 2014) PubMed
PEO	Found in cis with T251I and in trans w/W748S in a 50 y.o.with PEO and myopathy. In a study that suggests that dopaminergic neurons are vulnerable to the accumulation of somatic mtDNA damage, and defects of mtDNA replication and repair.		(Tzoulis et al., 2016) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in trans w/G848S and in cis w/T251I with PEO, muscle weakness, and cognitive impairment. Similar to SANDO, but no dysarthria.		(Bereau et al., 2016) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in trans w/S1095R and in cis w/T251I with PEO, muscle weakness, ataxia, and polyneuropathy. Similar to SANDO, but no dysarthria.		(Bereau et al., 2016) PubMed
SANDO	Found in trans w/R232H and H227L and in cis w/P587L in a 26 y.o. with PEO, cognitive impairment, ataxia, polyneuropathy, msucle weakness, migraines, dysphagia, and dysarthria.		(Bereau et al., 2016) PubMed
PEO	Found in cis with T251I and in trans w/A467T in a 30 y.o. with muscle weaknes and PEO.		(Bereau et al., 2016) PubMed
SANDO	Found in cis w/T251I and in trans w/R232H and H277L in a 40 y.o. with PEO, ataxia, polyneuropathy, and dysarthria.		(Bereau et al., 2016) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in trans w/R852C and in cis w/T251I in a 50 y.o. with PEO, muscle weakness, and polyneuropathy. Similar to SANDO, but no dysarthria.		(Bereau et al., 2016) PubMed
PEO	Found in trans w/A467T and in cis w/T251I in a 56 y.o. with PEO, muscle weakness, and dysphagia.		(Bereau et al., 2016) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in trans w/A467T and in cis w/T251I in a 58 y.o. with ataxia, sensory neuropathy, and dysphagia.		(Bereau et al., 2016) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in trans w/A467T and in cis w/T251I in a 66 y.o. with ataxia, sensory neuropathy, and PEO.		(Bereau et al., 2016) PubMed
PEO	Found in cis w/T251I on both allesls with ptosis and dysphagia		(Bereau et al., 2016) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in trans w/T251I and P587L with ataxia, sensory neruopathy, PEO, deafness, and dysphagia.		(Bereau et al., 2016) PubMed
PEO	Found in cis with T251I and in trans w/T989dup in a 36 y.o. female with cornieal edema and muscle weakness. One brother affected and has both variants and one unaffected sister with no mutations.	Not found in 100 random controls	(Pozzo et al., 2017) PubMed
Neuropathy w/ cataracts and glaucome	Found in trans with R943C and in cis withT25lI in an 8 mo. female with uppper and lower limb distal neuromyopathy with ragged red fiberes, cataracts. Later developed ophthalmoparesis, glaucoma, and muscle wasting.		(Castiglioni et al., 2018) PubMed
Neuropathy w/ cataracts and glaucome	Found in trans with R943C and in cis with T251I in an 24 mo. female with uppper and lower limb distal neuromyopathy with ragged red fiberes, cataracts. Later developed ophthalmoparesis, glaucoma, and muscle wasting.		(Castiglioni et al., 2018) PubMed
Late-onset MDS	Found as compound heterozygous in cis with T251I and in trans with R807C in a 70 year-old man presenting with a late onset sensory neuronopathy, chronic progressive external ophthalmoplegia, gait ataxia and parkinsonism.		(Meira et al., 2019) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: G588D cDNA Position: 1763 g→a (exon 10)
Disease	Genetics	Frequency	Reference
VPA induced liver failure	Found in trans w/ A467T in a 2 y.o. w/ VPA induced liver failure	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans w/ T251I and P587L in a 6 y.o. w/ no symptoms noted	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: P589L cDNA Position: 1766 c→t (exon 10)
Disease	Genetics	Frequency	Reference
Alpers	Found in cis w/P587L and in trans w/W748S.		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed

Amino Acid Substitution: L591F cDNA Position: 1774c→t (exon 10)
Disease	Genetics	Frequency	Reference
SANDO	Found in trans w/R1096C in a 48 y.o. female with SANDO and dysphagia.		(Kurt et al., 2012) PubMed

Amino Acid Substitution: R597W cDNA Position: 1789 c→t (exon 10)
Disease	Genetics	Frequency	Reference
PEO with ataxia	Homozygous		(Stewart et al., 2009) PubMed
PEO, seizures, and VPA induced liver failure	Found as a homozygote in an 18 y.o. with PEO, neuropathy, seizures, and VPA induced hepatotoxicity	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Encephalopathy and ataxia	Found in trans w/ A467T in a 26 y.o. w/ encephalopathy, ataxia, neuropathy, and ptosis.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
SANDO	Found in trans w/A467T in a 20 y.o. with ataxia, polyneuropathy, ophthalmoparesis, and dysarthria,		(Bereau et al., 2016) PubMed

Amino Acid Substitution: R597Q cDNA Position: 1790 g→a (exon 10)
Disease	Genetics	Frequency	Reference
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: T599P cDNA Position: 1795 a→c (exon 10)
Disease	Genetics	Frequency	Reference
SANDO	Found as a homozygous mutation in a 42 y.o. female with gait instability, dysarthria and foot numbness		(Richter et al., 2018) PubMed

Amino Acid Substitution: K601E cDNA Position: 1801 a→g (exon 10)
Disease	Genetics	Frequency	Reference
Sensory axonal neuronopathy	Found in a 67 y.o. female and her 61 y.o. brother. Found in compound w/Y837C, D122Y, Q1236H. Both patients have an ataxia, dysarthria, seizures, and sensory neuropathies.	Not found in 200 chromosomes controls	(Zabalza et al., 2014) PubMed

Amino Acid Substitution: M603L cDNA Position: 1807 a→t (exon 10)
Disease	Genetics	Frequency	Reference
PEO with ptosis	Found as compound in trans with T251I-P587L	24 patients diagnosed with mitochondrial disease and having multiple mtDNA deletions compared to 100 controls in a Spanish population.	(Gonzalez-Vioque et al., 2006) PubMed

Amino Acid Substitution: L605R cDNA Position: 1814_1815 tt→gc (exon 10)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans w/ A467T. Mitochondria depletion in liver		(Stewart et al., 2009) PubMed

Amino Acid Substitution: H613Y cDNA Position: 1837 c→t (exon 10)
Disease	Genetics	Frequency	Reference
Ptosis	Found as a heterozygous mutation in a 14 y.o. male with ptosis, myopathy, severe cerebellar atrophy, dysarthria, and mild cognitive impairment.		(Pozzo et al., 2017) PubMed

Amino Acid Substitution: Y614X cDNA Position: 1842 c→ a or g
Disease	Genetics	Frequency	Reference
	Reference # rs62640033		PubMed

Amino Acid Substitution: R617C cDNA Position: 1849 c→t (exon 10)
Disease	Genetics	Frequency	Reference
	Heterozygous with muscle weakness, exercise intolerance, hearing loss, arrhythmia		(Wong et al., 2008) PubMed

Amino Acid Substitution: G621D cDNA Position: 1862 g→a (exon 10)
Disease	Genetics	Frequency	Reference
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: L623W cDNA Position: 1868 t→g (exon 10)
Disease	Genetics	Frequency	Reference
Hypoketotic, hypyoglycaemial, and liver dysfunction	Compound heterozygote w/ K755E	Not found in 200 healthy controls	(Bortot, et al., 2009) PubMed
Hepatic disease	Found as heterozygous in trans with K755E with hepatic disease with neonatal onset and a dead sibling who carried the same mutations.		(Blazquez-Bermejo et al., 2019) PubMed

Amino Acid Substitution: P625R cDNA Position: 1874 c→g (exon 10)
Disease	Genetics	Frequency	Reference
Alpers	Found as a compound heterozygote w/ A467T in a 1 y.o. with epilepsy and liver failure.		(Baruffini et al., 2011) PubMed

Amino Acid Substitution: R627W cDNA Position: 1879 c→t (exon 10)
Disease	Genetics	Frequency	Reference
PEO	Found in trans w/A467T in a 39 y.o. male whose unaffected parents are hets for each mutation.	Van Goethem, 2003: absent in 612 Belgian controls.	(Van Goethem et al., 2003a)  PubMed
PEO	Found in trans w/ A467T in 2 PEO patients w/ hearing loss	Not found in 250 control individuals	(Horvath et al., 2006) PubMed
Alpers	Found in trans w/T914P		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed
Epilepsy	Found in compound with W748S in teenage sisters with epilepsy, encephalitis with mitochondrial abnormalities affecting neurons		(Nolte et al., 2013) PubMed
Encephalopathy, Seizure, Stroke	Found as homozygous in three unrelated South Asian probands with mitochondrial encephalopathy, seizures and stroke-like episodes.		(Paramasivam et al., 2019) PubMed

Amino Acid Substitution: R627Q cDNA Position: 1880 g→a (exon 10)
Disease	Genetics	Frequency	Reference
Ataxia - myopathy  PEO - ataxia - neuropathy Alpers	Found in cis with Q1236H and in trans with A467T  Found in compound in trans with R309H or R1096H in Alpers  Found in cis with Q1236H and in trans with L965stop-E1143G in PEO		(Luoma et al., 2005) PubMed
Ataxia - myopathy  PEO - ataxia - neuropathy Alpers	Found in cis with Q1236H and in trans with A467T  Found in compound in trans with R309H or R1096H in Alpers  Found in cis with Q1236H and in trans with L965stop-E1143G in PEO	Not found in 250 control individuals	(Horvath et al., 2006) PubMed
MELAS	Found w/ G848S; heterozygous mutation; w/ mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.		(Deschauer et al., 2007) PubMed
Ataxia Neuropathy	Found in cis w/ G11D and in trans w/ R852C.		(Wong et al., 2008) PubMed
Cerebellar ataxia, sensory neuropathy, PEO, and dysphagia	Found with G848S in a 35 yr. old patient		(Schulte et al., 2009) PubMed
Cerebellar ataxia, sensory neuropathy, PEO, and dysphagia	Found with T1199X ins. a at c.3594 in a 47 yr. old patient		(Schulte et al., 2009) PubMed
Cerebellar ataxia, sensory neuropathy, PEO, and dysphagia	Found with R1096C in a 43 yr. old patient		(Schulte et al., 2009) PubMed
Epilepsy and ataxia-neuropathy	Found as a compound heterozygote w/S305R in a 5 y.o. with epilepsy that developed ataxia and neuropathy in his teens.		(Baruffini et al., 2011) PubMed
Encephalopathy	Found in trans w/ R852C and G11D in a 25 y.o. w/ dementia, encephalopathy, and stroke.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
SANDO	Found w/A467T in a 50 y.o. male with ataxia, ptosis, diabetes and mtDNA deletions.		(Hanisch et al., 2014) PubMed
SANDO	Found in cis w/Q1236H and in trans w/W748S and E1143G in a 38 y.o. with sensory neuropathy, ataxia, PEO, and cognitive impairment.		(Bereau et al., 2016) PubMed
SANDO	Found in cis w/Q1236H and in trans w/W748S and E1143G in a 47 y.o. with sensory neuropathy, ataxia, Ophthalmoparesis and muscle weakness.		(Bereau et al., 2016) PubMed
Gait disturbance	Found as a heterozygote in a 61 y.o. male with ataxia, speech abnormalities, and swallowing abnormalities		(Vogel et al., 2017) PubMed
Gait disturbance	Found w/G848S in a 29 y.o. female with ataxia, speech abnormalities, and swallowing abnormalities		(Vogel et al., 2017) PubMed
mild ophthalmoparesis	Found in trans with G848S in a 33 y.o. male with sensory ataxia and neuroathy		(Pozzo et al., 2017) PubMed
SANDO	Found in trans with W748S. Exhibit cerebellar and proprioceptive ataxia, dysarthria, cognitive impairment and distal sensorimotor axonal neuropathy		(Gebus et al., 2018) PubMed

Amino Acid Substitution: R628Q cDNA Position: 1883 g→a (exon 10)
Disease	Genetics	Frequency	Reference
	Mutation found in one breast tumor heterozygous w/ the SNP R546C		(Singh et al., 2009) PubMed

Amino Acid Substitution: P648R cDNA Position: 1943 c→g (exon 10)
Disease	Genetics	Frequency	Reference
SANDO	Found in compound w/R807C in a 39 y.o. patient.		(Gago et al., 2006) PubMed
PEO + myopathy	ar, Found as either homozygous mutation or as compound in trans with R1096C in PEO.	Not found in 250 control individuals	(Horvath et al., 2006) PubMed
Ptosis and myopathy	Found in trans with T251I and P587L in a 59 y.o. male with dysphagia, dysphonia, myopathy, ptosis, and mtDNA deletions. Father had same symptoms.		(Ferreira et al., 2011) PubMed
SANDO	Found in trans with R807C in a 49 y.o. pt. with SANDO and mtDNA deletions		(Ferreira et al., 2011) PubMed
PEO	Found in trans with W585X in a 50 y.o. male with PEO, dysphagia, dysphonia, and parkinsonism with mtDNA deletions		(Ferreira et al., 2011) PubMed
Parkinsonism and SANDO	Found in trans w/R807C ina 52 y.o. male with ptosis, muscle weakness,dysphagia, and SANDO with mtDNA deletions and only 5% COX negative ragged red muscle fibers		(Miguel et al., 2014) PubMed
PEO	Found as a homozygous mutation in a 61 y.o. female with dysarthria, dysphagia, cataract, ataxia, polyneuropathy, thyropathy, and upper cerebellar cyst. Patient has mtDNA deletions and ragged red muscle fibers.		(Pozzo et al., 2017) PubMed
Neuropathy w/ cataracts and glaucome	Found with H932Y in a 1 y.o. male with uppper and lower limb distal neuromyopathy with ragged red fiberes, cataracts. Later developed strabismus, ptosis, glaucoma, and muscle weakness.		(Castiglioni et al., 2018) PubMed

Amino Acid Substitution: H659Q cDNA Position: 1977 c→g (exon 11)
Disease	Genetics	Frequency	Reference
	Reference # rs62640030		PubMed

Amino Acid Substitution: E662K cDNA Position: 1984 g→a (exon 11)
Disease	Genetics	Frequency	Reference
Neutral polymorphism		2.8% of 450 individuals	(GeneSNPs, 2004) PubMed

Amino Acid Substitution: Q666L cDNA Position: 1997 a→t (exon 11)
Disease	Genetics	Frequency	Reference
	Reference # rs62640029		PubMed

Amino Acid Substitution: R709X cDNA Position: 2125 c→t (exon 12)
Disease	Genetics	Frequency	Reference
PEO	Found as compound with T251I.		(Del Bo et al., 2003) PubMed
PEO	Found as compound with T251I-P587L in a pt. w/ mtDNA deletions.	Di Fonzo 2003: Not found in 100 DNA samples from healthy Italians	(Di Fonzo et al., 2003) PubMed

Amino Acid Substitution: Q715X cDNA Position: 2143 c→t (exon 12)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans w/ A467T		(Wong et al., 2008) PubMed
Encephalopathy	Found in trans w/ A467T in a 5 y.o. pt.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: c.2157+5_+6gc>ag cDNA Position: 2157 gc→ ag (exon 12)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans with A467T, most likely a splice site mutation.		(Wong et al., 2008) PubMed

Amino Acid Substitution: R722H cDNA Position: 2165 g→a (exon 13)
Disease	Genetics	Frequency	Reference
Neutral polymorphism		<1 % in control populations	(Luoma et al., 2007) PubMed
Myoclonic epilepsy			(Bolszak et al., 2009) PubMed
PEO, mtDNA deletions and neurological phenotypes	Homozygous in 3 siblings with mtDNA deletions, hearing loss, diabetes, dementia, dysphagia, and limb myopathy. Also found in trans w/ W748S in two siblings w/ ptosis, epilepsy, mental retardation	1:135 carrier frequency in a Finnish population	(Komulainen et al., 2010) PubMed
Alpers	Found in trans with V1044A in a 2.5 y.o. with epilepsy and encephalopathy	7 of 136 mitochondrial disease Finnish children, and screened against 370 control DNA samples	(Isohanni et al., 2011) PubMed
Parkinsonism	Found in a Chinese population with Parkinsonism at an allelic frequency of 0.033	344 Chinese parkinson patients and 144 controls	(Gui et al., 2012) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: H734R cDNA Position: 2201 a→g (exon 13)
Disease	Genetics	Frequency	Reference
	Reference # rs56119329		PubMed

Amino Acid Substitution: N736S cDNA Position: 2207 a→g (exon 13)
Disease	Genetics	Frequency	Reference
Ataxia, cardiomyopathy, and depression	Found in a 52 y.o. female with melancholic depression, unstable gailt, and dilated cardiomyopathy.		(Verhoeven et al., 2011) PubMed

Amino Acid Substitution: G737R cDNA Position: 2209 g→c (exon 13)
Disease	Genetics	Frequency	Reference
Epilepsy and liver failure	Found as compound in trans with A767D in two family members	Not found in 250 control individuals	(Horvath et al., 2006)  PubMed
Parkinsonism	Parkinsonism in trans with R853W.		(Davidzon et al., 2006) PubMed
Charcot-Marie Tooth disease, (CMT) (profound cerebellar ataxia)	Found in trans with the S64L-R232H in CMT.	Found in 2/666 (0.3%) of control alleles	(Harrower et al, 2008) PubMed
arPEO+ and Myocerebrohepatopathy (MCHS)	Found in trans w/ A467T. In trans w/ E1143G-R943C in MCHS.  Also, found as a single heterozygous mutation.		(Wong et al., 2008) PubMed
PEO	Found in trans with W748S.		(Tzoulis, et al., 2009) PubMed
PEO	Found in trans w/ L304R in a 54 y.o. with PEO, ptosis, and muscle weakness	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ G426S in an 11 y.o. w/ seizures and an abnormal MRI	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ V855L in an 8 mo. w/ seizures, liver failure, and developmentally delayed	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans A957V in a 4 mo. No symptoms noted	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Epilepsy	Found with A767D in a 1 y.o. male. Patient also had myopathy. In a study using patient fibroblasts, the cells were unable to up regulate mitochondrial biogenesis when exposed to Valproic acid.		(Sitarz et al., 2014) PubMed
Parkinsonism	Found in trans with R853W in a 32 y.o. female with early signs of Parkinsonism and COX negative muscle fibers. Levodopa-responsive.		(Rempe et al., 2016) PubMed
Charcot-Marie-Tooth disease	Found as compound heterozygous in trans with R309H in a 6 year-old girl with a complex phenotype that included early onset axonal Charcot?Marie?Tooth disease (CMT).		(Phillips et al., 2019) PubMed
MDS	Found in a large cohort study.		PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: N740D cDNA Position: 2218 a→g (exon 13)
Disease	Genetics	Frequency	Reference
	Reference # rs78347903		PubMed

Amino Acid Substitution: V742M cDNA Position: 2224 g→a (exon 13)
Disease	Genetics	Frequency	Reference
SNP	Reference # rs147827654		PubMed

Amino Acid Substitution: G746S cDNA Position: 2236 g→a (exon 13)
Disease	Genetics	Frequency	Reference
Ataxia, PEO	ar, Found in cis w/ E1143G, and in trans G848S	1in 454 alleles	(Stewart et al., 2009) PubMed
PEO	Found in trans w/G848S in a 36 y.o. male with PEO, peripheral neuropathy, and ataxia		(Lax et al., 2012a) PubMed

Amino Acid Substitution: W748C cDNA Position: 2244 g→t (exon 13)
Disease	Genetics	Frequency	Reference
MELAS	Found in trans w/ R309C in an 18 y.o. female with seizues, vision loss, neuropathy, ophthalmoparesis. Each parent is an unaffected heterozygote.		(Ching-wan et al., 2015) PubMed

Amino Acid Substitution: W748S cDNA Position: 2243 g→c (exon 13)
Disease	Genetics	Frequency	Reference
Ataxia	Found in compound w/E1143G w/ataxia, dysarthria, and cognitive impairment. Also found as a homozygous mutation.		(Van Goethem et al., 2004)  PubMed
Alpers	Found in compound w/ Y1210fs1216X and E1143G	Ferrari et al., 2005 reported 1 in 9 (11.11%) children with a combination of progressive neurological and hepatic failure, with a heterozygous frequency of 1% of Italian controls.	(Ferrari et al., 2005) PubMed
Hepatocerebral Syndrome	Found in 4 children in cis w/E1143G and in trans w/G848S.		(Davidzon et al., 2005) PubMed
Ataxia	Found as a homozygous mutation w/ E1143G	Carrier frequency in the general Finnish population of 1:125 from 500 control chromosomes	(Hakonen et al., 2005) PubMed
Alpers	Found in trans w/E1143G and in cis w/G848S in a 13 mo. old male		(Nguyen et al., 2005) PubMed
Ataxia Syndrome	Found in trans w/Q497H in patients w/ progressive ataxia and epilepsy	1 in 97 found in healthy controls and 1 in 99 found mtDNA disease patients	(Winterthun et al., 2005)  PubMed
PEO	Found in trans w/A467T and also in trans w/ Q308H	Not found in 250 control individuals	(Horvath et al., 2006) PubMed
SCAE	Found in trans w/L304R in a 20 y.o. female w/ spinocerebellar ataxia epilepsy syndrome and mtDNA deletions	Not found in 300 healthy French control chromosomes	(Naimi et al., 2006) PubMed
PEO, ataxia, and epilepsy	Found as a homozygous mutation in 13 pts. ranging in age from 2 to 19 yrs. One heterozygous 55 y.o. pt. with epilepsy. Also found in trans w/A467T in 7 pts. Ranging in age from 14 to 36 yrs. All w/ wide spectrum of mitochondrial disease.	Studied in 26 mitochondrial disease patients	(Tzoulis et al., 2006) PubMed
Ataxia Neuropathy	A biochemical study of W748S pol gamma which exhibited low DNA polymerase activity, low processivity and a severe DNA-binding defect, and is commonly found in cis w/E1143G		(Chan et al., 2006)  PubMed
Alpers	Found in cis w/K561M and found in cis with E1143G. Both patients had mtDNA depletion	Sarzi, et al. 2007 reported 2% (n=50) of patients with multiple respiratory chain deficiency with a 35% decrease of mtDNA were found with the mutation W748S with E1143G.	(Sarzi, et al. 2007) PubMed
Alpers, Ataxia Neuropathy, and arPEO+	Found in trans w/ G848S, and in cis w/ Q479H-E1143G. Also found in trans w/ A467T. arPEO+ as a compound w/ E1143G		(Wong et al., 2008) PubMed
Alpers	Homozygous, juvenile onset		(Uusimaa et al., 2008) PubMed
Alpers	Found in trans w/ [R852C and G11D], and found in 2 additional pts. in trans w/T914P. Found homozygous in one pt. Found in trans w/ G848S. Found in trans w/[P587L and P589L].		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed
PEO and Alpers	Found in trans w/ A467T. In a 2nd pt., found in cis w/ E1143G and in trans w/ G11D and R852C.		(Stewart et al., 2009) PubMed
Alpers	In cis w/E1143G and in trans w/ G484S		(Taanman et al., 2008) PubMed
mtDNA depletion	In cis w/E1143G and in trans w/ H1110Y and Q1236H		(Taanman et al., 2008) PubMed
Alpers	In cis w/ Q497H and E1143G, and in trans w/ G848S	Found in one child w/ a normal brain MRI	(Brunetti-Pierri et al., 2008) PubMed
Alpers	Found in 2 infants in trans w/ Y1210X		(Spinazzola et al., 2009) PubMed
Alpers	Found in trans w/ L244P		(Spinazzola et al., 2009) PubMed
Alpers	Found in trans w/ D930N		(Spinazzola et al., 2009) PubMed
Parkinsonism	Homozygous mutation w/ PEO, ataxia, peripheral neuropathy, and hearing loss		(Remes et al., 2009) PubMed
Leigh Syndrome	Found in trans with G11D and R852C		(Naess, et al., 2009) PubMed
PEO	Found in trans with G737R, and in a 2nd pt. in cis with P587L and in trans with T251I.		(Tzoulis, et al., 2009) PubMed
PEO, ptosis, polyneuropathy, ataxia, and dysartria	Found in trans w/A467T and in compound w/ E1143G	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Epilepsy, myoclonus, polyneuropathy, ataxia, and cognitive delay; a 2nd pt. with epilepsy and MELAS-like symptoms	Found in trans w/ A467T.	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Cerebellar ataxia, sensory neuropathy, PEO, and dysphagia	Found with A467T in 4 middle aged patients, 2 of which are sisters		(Schulte et al., 2009) PubMed
Cerebellar ataxia, sensory neuropathy, PEO, and dysphagia	Homozygous in a 39 yr. old patient		(Schulte et al., 2009) PubMed
Hepatocerebral - Alpers symptoms	Found w/P1073L. Psychomotor delay, seizures, liver delay, and gastrointestinal dysmotility		(Kurt et al., 2010) PubMed
SANDO	Found in trans w/ P1073L. Psychomotor delay, seizures, liver delay, and gastrointestinal dysmotility		(Posada et al., 2010) PubMed
PEO, mtDNA deletions and neurological phenotypes	Found in trans with A467T and in cis with E1143G. Sensory ataxia, dysarthria, and opthalmoplegia.	1:135 carrier frequency in a Finnish population	(Komulainen et al., 2010) PubMed
Alpers	Homozygous in 3 siblings with mtDNA deletions, hearing loss, diabetes, dementia, dysphagia, and limb myopathy. Also found in trans w/ R722H in two siblings w/ Ptosis, epilepsy, mental retardation	7 of 136 mitochondrial disease Finnish children, and screened against 370 control DNA samples	(Isohanni et al., 2011) PubMed
Alpers	Found in cis with E1143G and in trans with R807C in a 1 y.o. with epilepsy and encephalopathy	7 of 136 mitochondrial disease Finnish children, and screened against 370 control DNA samples	(Isohanni et al., 2011) PubMed
Alpers	Found in cis with E1143G and Q497H, and in trans with A467T in a 6 y.o. with epilepsy and encephalopathy	7 of 136 mitochondrial disease Finnish children, and screened against 370 control DNA samples	(Isohanni et al., 2011) PubMed
Alpers	Found in cis with E1143G and in trans with G848S in a 11 mo. old with epilepsy and encephalopathy	7 of 136 mitochondrial disease Finnish children, and screened against 370 control DNA samples	(Isohanni et al., 2011) PubMed
Alpers	Found in cis with 1143G and in trans with T914P in a 2.5 y.o. with epilepsy and encephalopathy	7 of 136 mitochondrial disease Finnish children, and screened against 370 control DNA samples	(Isohanni et al., 2011) PubMed
Ataxia and cerebellar atrophy	Found as a homozygote in a 30 y.o. pt. with peripheral neuropathy, ataxia, and fatigability	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
SANDO and PEO	Found in trans w/ A467T in a 54 y.o. with PEO, ptosis, ataxia, neuropathy, and SANDO	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ A467T in a 16 y.o. with seizures, dystonia, choria, neuropathy, and ptosis	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found in a 25 y.o. pt. that is homozygous for the W748S mutation and S28C as a heterozygote with PEO, ataxia, ptosis, and hearing loss	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans w/ D892fsX39 in a 9 mo. old pt. w/ a deceased sibling	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ G848S in a 5 y.o. pt. w/myclonic seizures, liver failure, and hypotonia	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Alpers	Found in trans w/ Q449X in a 21 y.o. with seizures	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ G848S in a 7 y.o. w/ seizures and cortical blindness	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans w/ G848S in a 3 y.o.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans w/ G8484S in a 6 y.o. pt. with GI issues and irregular occipital lobe. Sibling died from VPA induced organ failure.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/A467T in an 18 y.o. with ataxia, seizures, dystonia, and optic atrophy.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found in trans w/ R953C in a 51 y.o. w/ peripheral neuropathy, ptosis, hypotonia, ataxia, and seizures.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ T914P in a 5 y.o. w/ seizures	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ T914P in an 8 mo. w/ seizures, hypotonia, abnormal MRI, and developmentally delayed.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans w/ A467T in a 29 y.o. symptoms not noted	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures and liver failure	Found in trans w/ M797del in a 1 y.o. with seizures and hepatic failure	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures and liver failure	Found in trans w/ G888D in a 2 y.o. w/ seizures, hepatic failure, ketosis and abnormal MRI	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Alpers	Found in trans w/ R852H in a 3 y.o. w/ Alpers	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
MSCAE	Found in trans w/ T914P in a 15 y.o. female with mitochondrial spinocerebellar ataxia and epilepsy.		(Hinnell et al., 2012) PubMed
Alpers	Found in trans w/G848S in a 6 yr. 4 mo. with microvesicular fatty changes of the liver, myclonic seizures, and ataxia		(Hunter et al., 2011) PubMed
Alpers	found in trans w/G8484S in a 6 yr. 9 mo. with seizures, developmentally delayed, and ataxia.		(Hunter et al., 2011) PubMed
Alpers	Found w/ E1143G and R232H in a pediatric patient w/mitochondrial encephalomyopathy, seizures, ataxia, and ophthalmological involvement		(Sofou et al., 2012) PubMed
Alpers	Found w/M1163R and E1143G in a pediatric patient w/mitochondrial encephalomyopathy, seizures, ataxia, and ophthalmological involvement		(Sofou et al., 2012) PubMed
MNGIE-like	Found in a 25 y.o. female as a homozygous mutation. Patient had migraines, ptosis, PEO, exercise intolerance, peripheral neuropathy, and ataxia.		(Tang et al., 2012) PubMed
MNGIE-like	Found in compound with R953C in a 50y.o. male with cognitive impairment, muscle weakness, diarrhea, vomiting, ptosis, and opthalmoparesis.		(Tang et al., 2012) PubMed
Alpers and PEO	Found in trans with R852C in a pediatric female patient with hypotonia, developmental delay, ataxia, and seizures		(Vasta et al., 2012) PubMed
MIRAS	Mother and son were homozygous for E1143G in cis with E1143, and the unaffected father was heterozygous for W748S in cis with E1143G. Both mother and son had decreased mtDNA and spinocerebellar ataxias with presentation in late 30's and early 40's.	Frequencies in Europe for W748S+E1143G or A467T range from 0.6% in Belgium, 0.8% in Finland, and 2% in Finland	(Palin et al., 2012) PubMed
Torticollis and PEO	Found in trans w/A467T in a 43 y.o. female with abnormal gait, ataxia, PEO, and head jerks.		(Tuladhar et al., 2012) PubMed
Parieto-occipital lobe epilepsy	Found in trans w/ A467T in a 16 y.o. female with seizures, headaches, cerebellar ataxia, axonal neuropathy, visual impairment, and impaired cognitive function		(Roshal et al., 2011) PubMed
PEO	Found in trans w/A467T in a 24 y.o. female with arPEO, cerebellar ataxia, and mtDNA deletions		(Lax et al., 2012b) PubMed
PEO	Found in trans w/ R1096C in a 49 y.o. male with PEO, ptosis, epilepsy and peripheral neuropathy		(Lax et al., 2012a) PubMed
PEO	Found in trans w/ A467T in a 47 y.o. male with arPEO, ptosis and sensory neuropathy		(Lax et al., 2012a) PubMed
PEO	Found in trans w/A467T in a 48 y.o. male with PEO, ptosis, ataxia and sensory neuropathy		(Lax et al., 2012a) PubMed
Epilepsy	Found in trans w/A467T in a 18 y.o.female male with epilepsy, ataxia and sensory neuropathy		(Lax et al., 2012a) PubMed
Epilepsy	Found in trans w/A467T in a 20 y.o. female male with epilepsy, ataxia and sensory neuropathy		(Lax et al., 2012a) PubMed
	Found in a Chinese population with Parkinsonism at an allelic frequency of 0.391	344 Chinese parkinson patients and 144 controls	(Gui et al., 2012) PubMed
Epilepsy	Found in compound with R627W in teenage sisters with epilepsy, encephalitis with mitochondrial abnormalities affecting neurons		(Nolte et al., 2013) PubMed
PEO	Found in compound with L304R in a 27 yo female with sensory and cerebellar ataxia, axonal sensory neuropathy	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
Epilepsy	Found in compound with A467T in a 17 yo female with axonal neuropathy, cerebellar ataxia, and hyperintensity of rolandic,	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
Epilepsy	Found in compound with T914P in a 6 yo male with epilepsy and hepatic cholestasis and cytolysis, and mtDNA deletions	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
SANDO	Found as a homzygous mutation in a 37 yo male with SANDO, parkinsonism, and mtDNA deletions	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
Epilepsy	Found as a heterozygous mutation in a 2 yo female with epilepsy, delayed psychomotor development, and mtDNA deletions and depletion.	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
Encephalopathy	Found as a heterozygous mutation with A467T in 2 patients with PEO and ataxia.		(Tzoulis et al., 2013) PubMed
Encephalopathy	Found as a homozygous mutation in 7 patients with ataxia, epilepsy, and PEO		(Tzoulis et al., 2013) PubMed
Epilepsy	Found with deletion of a" t" at c.3600 in a 3 y.o. female. Patient also had myopathy. In a study using patient fibroblasts, the cells were unable to up regulate mitochondrial biogenesis when exposed to Valproic acid.		(Sitarz et al., 2014) PubMed
MIRAS	Found with A467T in a 39 y.o. male. Patient also had Ataxia, PEO, and neuropathy. In a study using patient fibroblasts, the cells were unable to up regulate mitochondrial biogenesis when exposed to Valproic acid.		(Sitarz et al., 2014) PubMed
MIRAS	Found as a homozygous mutation in a 36 y.o. male with Ataxia, neuropathy, and PEO. . In a study using patient fibroblasts, the cells were unable to up regulate mitochondrial biogenesis when exposed to Valproic acid		(Sitarz et al., 2014) PubMed
Alpers	Found w/E1143G in a 16 mo. boy with epilepsy, mtDNA depletion, and noted defects of the respiratory chain complexes I,II, and IV.		(de Camaret et al., 2014) PubMed
Charcot-Marie Tooth Disease	Found w/Q497H in a Norweign family with Charcot-Marie Tooth Disease.	Total of 245 affected persons from 116 Charcot-Marie tooth disease families in Akershus County Norway.	(Hoyer et al., 2014) PubMed
SANDO	Found w/A467T in a 37 y.o. female with ataxia, ptosis, seizures, and mtDNA deletions.		(Hanisch et al., 2014) PubMed
SANDO	Found w/A467T in a 56 y.o. male with ataxia, ptosis, diabetes, and mtDNA deletions.		(Hanisch et al., 2014) PubMed
SANDO	Found w/A467T in a 56 y.o. male with ataxia, ptosis, diabetes and mtDNA deletions.		(Hanisch et al., 2014) PubMed
SANDO	Found w/A467T in a 45 y.o. male with ataxia, ptosis, diabetes and mtDNA deletions.		(Hanisch et al., 2014) PubMed
Encephalopathy and PEO	Found as a homozygous mutation in a 6 y.o. w/epilepsy, ataxia, and neuropathy		(Tzoulis et al., 2014) PubMed
Encephalopathy	Found as a homozygous mutation in a 15 y.o. w/epilepsy, ataxia, and neuropathy		(Tzoulis et al., 2014) PubMed
Encephalopathy and PEO	Found as a homozygous mutation in a 17 y.o. w/epilepsy, ataxia, and neuropathy		(Tzoulis et al., 2014) PubMed
Encephalopathy and PEO	Found as a homozygous mutation in a 12 y.o. w/epilepsy, ataxia, and neuropathy		(Tzoulis et al., 2014) PubMed
Encephalopathy	Found as a homozygous mutation in a 2 y.o. w/epilepsy, ataxia, and neuropathy		(Tzoulis et al., 2014) PubMed
Encephalopathy and PEO	Found as a homozygous mutation in a 16 y.o. w/epilepsy, ataxia, and neuropathy		(Tzoulis et al., 2014) PubMed
Encephalopathy and PEO	Found as a homozygous mutation in a 15 y.o. w/epilepsy, ataxia, and neuropathy		(Tzoulis et al., 2014) PubMed
Alpers	Found as a heterozygous mutation with the 2nd POLG1 allel completely deleted. The patient was a 2 y.o. Swedish male with impaired motor skills, epileptic seizure, and died from VPA induced liver failure.		(Naess, et al., 2011) PubMed
PEO	Found in compound w/A143V and E1143G in a 40 y.o. female patient w/ chronic intestinal pseudo-obstruction, PEO, and ataxia.	In 5 out of 80 patients w/ chronic intestinal pseudo-obstruction	(Amiot et al., 2009) PubMed
Hypertrophic olivary degeneration	Found as a homozygous mutattion in a 30 y.o. male with hepatitis C and hearing loss, slurred speech, gait ataxia		(Arkadir et al., 2015) PubMed
Progressive ataxia and Palatal tremor (PAPT)	Found in trans w/I1185N in a 52 y.o. male w/ kinetic and static ataxia, dysarthria, palatal trmor, and vertical nystagmus.		(Nicastro et al., 2016) PubMed
Migrains, siezures, and ataxia	Found as a compound heterozygote w/ A467T in a 22 y.o. female with epileptic siezures, migrains and ataxia. Her brother presented with siezures at 19 yrs. w/ same mutations.		(Vinjam et al., 2015) PubMed
fragile X tremor/ataxia syndrome (FXTAS)	Found as a homozygous mutation in a 60 y.o. Swedish male with balance and gait difficulties, slurred speech, diplopia and cognitive decline. Negative for Fragile X Syndrome.		(Paucar et al., 2016) PubMed
Ataxia neuropathy	Found as a homozygote in a 29 y.o. women with PEO, general areflexia, and abnormal leg pallesthesia. MRI showed lesions in the thalamus, cerebellum, and inferior olivary nucleus.		( Henao et al., 2016) PubMed
PEO	Found in trans with T251I and P587L in a 50 y.o.with PEO and myopathy. In a study that suggests that dopaminergic neurons are vulnerable to the accumulation of somatic mtDNA damage, and defects of mtDNA replication and repair.		(Tzoulis et al., 2016) PubMed
MSCA	Found as a homozygote in a 16 y.o.with encephalopathy, Epilepsy, SLE, ataxia, and myopathy. In a study that suggests that dopaminergic neurons are vulnerable to the accumulation of somatic mtDNA damage, and defects of mtDNA replication and repair.		(Tzoulis et al., 2016) PubMed
MSCAE	Found as a homozygote in a 12 y.o.with encephalopathy, ataxia, and myopathy. In a study that suggests that dopaminergic neurons are vulnerable to the accumulation of somatic mtDNA damage, and defects of mtDNA replication and repair.		(Tzoulis et al., 2016) PubMed
MSCAE	Found as a homozygote in a 17 y.o.with encephalopathy, Epilepsy, SLE, ataxia, and myopathy. In a study that suggests that dopaminergic neurons are vulnerable to the accumulation of somatic mtDNA damage, and defects of mtDNA replication and repair.		(Tzoulis et al., 2016) PubMed
MSCA	Found in trans with A467T in a 24 y.o.with encephalopathy, ataxia, and myopathy. In a study that suggests that dopaminergic neurons are vulnerable to the accumulation of somatic mtDNA damage, and defects of mtDNA replication and repair.		(Tzoulis et al., 2016) PubMed
MSCA	Found in trans with A467T in a 36 y.o.with encephalopathy, ataxia, and myopathy. In a study that suggests that dopaminergic neurons are vulnerable to the accumulation of somatic mtDNA damage, and defects of mtDNA replication and repair.		(Tzoulis et al., 2016) PubMed
MSCA	Found in trans with A467T in a 40 y.o.with encephalopathy, ataxia, and myopathy. In a study that suggests that dopaminergic neurons are vulnerable to the accumulation of somatic mtDNA damage, and defects of mtDNA replication and repair.		(Tzoulis et al., 2016) PubMed
MSCAE	Found in trans with A467T in a16 y.o.with encephalopathy, epilepsy, SLE, and ataxia. In a study that suggests that dopaminergic neurons are vulnerable to the accumulation of somatic mtDNA damage, and defects of mtDNA replication and repair.		(Tzoulis et al., 2016) PubMed
SANDO	Found in trans w/A467T with PEO, deafness, migraines, and depression.		(Bereau et al., 2016) PubMed
SCAE	Found in trans w/E1143G on both allels in a 22 y.o. with cerebellar ataxia, seizures, deafness, migraines, and dystonia		(Bereau et al., 2016) PubMed
SCAE	Found in trans w/L304R with PEO, cognitive impairment, seizures, ataxia, polyneuropathy, dysphagia, and dysarthria.		(Bereau et al., 2016) PubMed
SCAE	Found in trans with A467T and in cis E1143G in a 36 y.o. with PEO, ataxia, sensory neuropathy, seizures, and migraines.		(Bereau et al., 2016) PubMed
SANDO	Found as a homozygous mutation in a 37 y.o. with Parkinsonism, sensory neuropathy, ataxia, and PEO.		(Bereau et al., 2016) PubMed
SANDO	Found in cis w/E1143G and in trans w/ R627Q and Q1236H in a 38 y.o. with sensory neuropathy, ataxia, PEO, and cognitive impairment.		(Bereau et al., 2016) PubMed
SANDO	Found in trans w/R627Q and Q1236H and in cis w/E1143G in a 47 y.o. with sensory neuropathy, ataxia, Ophthalmoparesis and muscle weakness.		(Bereau et al., 2016) PubMed
SANDO	Found as a homozygous mutation in a 50 y.o. with sensory neuropathy, ataxia, cognitive impairment and PEO.		(Bereau et al., 2016) PubMed
Gait disturbance	Found w/ A467T in a 26 y.o. female with ataxia, speech abnormalities, and swallowing abnormalities		(Vogel et al., 2017) PubMed
Gait disturbance	Found w/ A467T in a 36 y.o. female with ataxia, speech abnormalities, and swallowing abnormalities		(Vogel et al., 2017) PubMed
Gait disturbance	Found as a heterozygote in a 22 y.o. female with ataxia, speech abnormalities, and swallowing abnormalities		(Vogel et al., 2017) PubMed
Gait disturbance	Found w/A467T in a 49 y.o. female with ataxia, speech abnormalities, and swallowing abnormalities		(Vogel et al., 2017) PubMed
Gait disturbance	Found as a heterozygous mutation in a 29 y.o. female with ataxia, speech abnormalities, and swallowing abnormalities		(Vogel et al., 2017) PubMed
Gait disturbance	Found w/A467T in a 41 y.o. female with ataxia, speech abnormalities, and swallowing abnormalities		(Vogel et al., 2017) PubMed
PEO	Found in trans with A847T in a 49 y.o. male with muscle weakness and sensory neuropathy. Patient has mtDNA deletions, COX negative muscle fibers, and ragged red fibers.		(Pozzo et al., 2017) PubMed
Cerebellar ataxia and sensory neuropathy	Found as a homozygous mutation in a 40 y.o. male with dysphagia, ataxia, neuropathy, and loss of vibration sense dysarthria		(Pozzo et al., 2017) PubMed
Ataxia	Found as a homozygous mutation in a 60 y.o. Swedish male with balance and gait difficulties, slurred speech, diplopia and cognitive decline. Negative for Fragile X Syndrome.		(Paucar et al., 2016) PubMed
Ataxia and palatal tremor	Found in trans with I1185N in a 52 y.o. male with diabetes, hypertension, and progressive gait and balance difficulties		(Nicastro et al., 2016) PubMed
SANDO	Found in trans w/A467T in a 50 y.o female with multisystem degeneration and cerebellar ataxia. Patient was symptomatic in her 20's which progressed to SANDO. Patient died of sudden cardiac arrest at the age of 50.		(Kirschenbaum et al., 2017) PubMed
Cerebellar ataxia	Homozygous W748S found in two sisters with cerebellar ataxia plus elevated cerebrospinal free sialic acid (CAFSA).		(Del Mar Amador et al., 2018) PubMed
SANDO	Found in trans with R627Q. Exhibit cerebellar and proprioceptive ataxia, dysarthria, cognitive impairment and distal sensorimotor axonal neuropathy		(Gebus et al., 2018) PubMed
Alpers	Homozygous W748S found in one baby		(Hayhurst et al., 2019) PubMed
MDS	Found as heterozygous in trans with G848S with peripheral neuropathy, transient hepatic dysfunction, and progressive encephalopathy with ataxia and psychiatric symptoms		(Blazquez-Bermejo et al., 2019) PubMed
late onset sensory axonal neuropathy	Found as homozygous in a 54?year?old woman with late onset sensory axonal neuropathy resulted from uniparental disomy of the long arm of chromosome 15.		(Phillips et al., 2019) PubMed
Hepatocerebral MDS	Found in trans with R807C or Y1210X or W748S or R869X or N1053fsX6. All infants died of liver faiture.		Pronicki et al., 2018) PubMed
MDS	Found in a large cohort study as homozygous or heterzygous in trans with A467T.	Homozygous variant 13% in early onset, 51% Juvenile/adult onset, 5% late onset. Heterzygous variants in trans with A467T 6% in early onset, 23% Juvenile/adult onset, 5% late onset.	(Hikmat et al., 2020) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: F749S cDNA Position: 2246 t→c (exon 13)
Disease	Genetics	Frequency	Reference
Alpers	Found in compound with A467T	Not found in 300 control chromosomes	(Nguyen et al., 2006) PubMed
PEO	Found in trans w/ c.3104 +3a→t in a 66 y.o. w/ PEO, ptosis, myopathy, and muscle weakness	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ A467T in a 6 y.o. w/ seizures	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans w/ A467T in an 8 mo. symptoms not noted	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Optic atrophy	Found in trans w/c.3104+3A>T in a 65 y.o. male with ptosis, dysphagia, exercise induced myalgia, limb weakness, and diabetes.		(Milone et al., 2011) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: L752P cDNA Position: 2255 t→c (exon 13)
Disease	Genetics	Frequency	Reference
Epilepsy, seizures, VPA induced liver failure	Found in trans w/W748S and E1143G		(Zsurka, et al., 2008) PubMed
Inclusion body myositis	Found as a heterozygous mutation in a Swedish patient with Inclusion body myostitis. In addition the patient had COX deficient muscle fibers, ragged red fibers, and mtDNA deletions.	1 in 26 patients with inclusion body myositis. 8 of which had heterozygous POLG mutations.	(Lindgen et al., 2015) PubMed

Amino Acid Substitution: H754Q cDNA Position: 2262 c→g (exon 13)
Disease	Genetics	Frequency	Reference
Seizures and hepatic failure	Found in trans w/ A467T in 2 y.o. w/ seizures, hepatic failure, cerebellar atrophy, and developmentally delayed	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: K755E cDNA Position: 2263 a→g (exon 13)
Disease	Genetics	Frequency	Reference
Hypoketotic, hypyoglycaemial, and liver dysfunction	Compound heterozygote w/ L623W	Not found in 200 healthy controls	(Bortot, et al., 2009) PubMed
Hepatic disease	Found as heterozygous in trans with L623W with hepatic disease with neonatal onset and a dead sibling who carried the same mutations.		(Blazquez-Bermejo et al., 2019) PubMed

Amino Acid Substitution: K755T cDNA Position: 2264 a→c (exon 13)
Disease	Genetics	Frequency	Reference
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: G763R cDNA Position: 2287 g→c (exon 14)
Disease	Genetics	Frequency	Reference
MNGIE-like	Found as a homozygous mutation in a 17 y.o. with PEO, polyneuropathy,and gastro-intestinal dysmotility		(Bereau et al., 2016) PubMed
PEO, SANDO	ar, Found as a homozygous mutation in PEO-SANDO	Not found in 500 ethnically-matched control chromosomes	(Santoro et al., 2006) PubMed

Amino Acid Substitution: P765T cDNA Position: 2293 c→a (exon 14)
Disease	Genetics	Frequency	Reference
Ataxia neuropathy spectrum and gastroparesis	Found as a homozygous mutation in a 52 y.o. woman with ptosis, ataxia neuropathy, gastroparesis, and opthalmoplegia		(Bostan et al., 2012) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: P765L cDNA Position: 2294 c→t (exon 14)
Disease	Genetics	Frequency	Reference
Hepaticencephalopathy, Alpers-Huttenlocher	Found as compound heterzygous in trans with R953P in a two year old girl.		(Dai et al., 2019) PubMed

Amino Acid Substitution: A767D cDNA Position: 2300 c→a (exon 14)
Disease	Genetics	Frequency	Reference
Alpers	Found as compound in trans with G737R	Not found in 250 control individuals	(Horvath et al., 2006) PubMed
Epilepsy	Found with G737R in a 1 y.o. male. Patient also had myopathy. In a study using patient fibroblasts, the cells were unable to up regulate mitochondrial biogenesis when exposed to Valproic acid.		(Sitarz et al., 2014) PubMed

Amino Acid Substitution: K768E cDNA Position: 2302 a→g (exon 14)
Disease	Genetics	Frequency	Reference
neuropathy and ataxia	Found in compound with M464T in a teenage female with axonal sensorimotor neuropathy and sensory ataxia with multiple mtDNA deletions	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed

Amino Acid Substitution: A781T cDNA Position: 2341 g→a (exon 14)
Disease	Genetics	Frequency	Reference
Ptosis, PEO	Found as heterozygous in trans with R627W in a 41-year-old male with ptosis, progressive external ophthalmoplegia (PEO), proximal myopathy, and sensorineural hearing loss aged 27?years.		(Paramasivam et al., 2019) PubMed

Amino Acid Substitution: G785fs21X cDNA Position: 2354 ins g stop @ 806 (exon 14)
Disease	Genetics	Frequency	Reference
PEO	ar, Compound with T251I	Absent in 100 control DNA samples	(Lamantea et al., 2002) PubMed

Amino Acid Substitution: R790H cDNA Position: 2369 g→a (exon 14)
Disease	Genetics	Frequency	Reference
SNP	Reference # rs191490663	4 in 10,000 individuals are heterozygous w/WES data. 1.82% in Puerto Rican population	PubMed
Alpers	Found as a heterzygous mutation in one patient w/Alpers	2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: M797del cDNA Position: 2391-2393 gat de (exon 14)
Disease	Genetics	Frequency	Reference
Seizures and liver failure	Found in trans w/ W748S in a 1 y.o. with seizures and hepatic failure	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: S799A cDNA Position: 2396 c → a (exon 14)
Disease	Genetics	Frequency	Reference
MNGIE-like syndrome	Found as heterozygous in trans with c.3643 + 1G > A (splicing) in a 42 years-old man with MNGIE-like syndrome involved leukoencephalopathy.		(Huang et al., 2019) PubMed

Amino Acid Substitution: A804T cDNA Position: 2410 g→a (exon 14)
Disease	Genetics	Frequency	Reference
Fatigue, muscle complaints, and bulbar dysarthria	ar, found in one 55 yr. old pt.	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed

Amino Acid Substitution: R807H cDNA Position: 2420 g→a (exon 14)
Disease	Genetics	Frequency	Reference
Seizures and hepatic failure	Found in trans w/ A467T in a 1 y.o. with seizures, hepatic failure, hypotonia, and failure to thrive	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: R807P cDNA Position: 2420 g→c (exon 14)
Disease	Genetics	Frequency	Reference
PEO	Sporadic Compound with T251I		(Del Bo et al., 2003) PubMed
PEO	Found in compound w/T251I/ P587L in1 pt. The study includes 31 mitochondrial myopathy patients w/ mtDNA deletions.	Di Fonzo 2003: Not found in 100 DNA samples from healthy Italians	(Di Fonzo et al., 2003) PubMed

Amino Acid Substitution: R807C cDNA Position: 2419 c→t (exon 14)
Disease	Genetics	Frequency	Reference
SANDO	Found in compound w/P648R in a 39 y.o. patient.		(Gago et al., 2006) PubMed
Alpers	Found in trans with E1143G and W748S in a 1 y.o. with epilepsy and Encephalopathy		(Isohanni et al., 2011) PubMed
Ptosis and myopathy	Found as a heterozygous mutation in a 74 y.o. male with myopathy, ptosis, and diplopia		(Ferreira et al., 2011) PubMed
SANDO	Found in trans with P648R in a 49 y.o. pt. with SANDO and mtDNA deletions.		(Ferreira et al., 2011) PubMed
Liver failure	Found in trans w/ A467T in a 1 y.o. w/ encephalopathy, liver failure, and lactic acidosis	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Parkinsonism and SANDO	Found in trans w/P648R ina 52 y.o. male with ptosis, muscle weakness,dysphagia, and SANDO with mtDNA deletions and only 5% COX negative ragged red muscle fibers		(Miguel et al., 2014) PubMed
Hepatocerebral MDS	Found in trans with W748S. This infant died at 23 months and had seizures and liver failure triggered by VPA.		Pronicki et al., 2018) PubMed
Late-onset MDS	Found as compound heterozygous in trans with T251I and P587L in a 70 year-old man presenting with a late onset sensory neuronopathy, chronic progressive external ophthalmoplegia, gait ataxia and parkinsonism.		(Meira et al., 2019) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: 4.7kb deletion of exons 15-21 cDNA Position: Intronic deletion starting in intron 14 (87,662,154) thru intron 21 (87,666,650), excising exons 15-21.
Disease	Genetics	Frequency	Reference
Alpers	Found as a compound heterozygote w/ A467T. Patient had early on set of Alpers and died at the age of 3.5 y.o.. The father carried the A467T mutation, and the mother the deletion.		(Compton et al., 2010) PubMed
Alpers	Found as a compound heterozygote w/ A467T in a 3.5 y.o. The father carried the A467T mutation, and the mother the deletion.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al. 2011) PubMed
Alpers	Found in trans w/A467T in a 2 y.o. w/seizures, developmentally delayed, and ataxia		(Hunter et al., 2011) PubMed

Amino Acid Substitution: c. 2480+1g>a cDNA Position: 2480+1 g→a splice site (exon 15)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans w/ W748S-E1143G		(Wong et al., 2008) PubMed

Amino Acid Substitution: IVS15-9- c.2485del 12bp cDNA Position: 2485 del 12bp (exon 16)
Disease	Genetics	Frequency	Reference
Alpers	Splice site mutation 3'exon15/intron junction, Found in trans with A467T	Not found in 250 control individuals	(Horvath et al., 2006) PubMed

Amino Acid Substitution: IVS16-10 c>t cDNA Position: IVS16-10 c>t (exon 16)
Disease	Genetics	Frequency	Reference
Cerebellar ataxia, sensory neuropathy, and dysphagia	Homozygous. Found in a 60 y.o. patient		(Schulte et al., 2009) PubMed

Amino Acid Substitution: Y831F cDNA Position: 2492 a→t (exon 16)
Disease	Genetics	Frequency	Reference
	Reference # rs41549716		PubMed

Amino Acid Substitution: Y831S cDNA Position: 2492 a→c (exon 16)
Disease	Genetics	Frequency	Reference
	Reference # rs41549716		PubMed

Amino Acid Substitution: Y831C cDNA Position: 2492 a→g (exon 16)
Disease	Genetics	Frequency	Reference
Epilepsy, exericise intolerance, and hearing loss	Found in a 6 y.o. female with mtDNA deletions in muscle tissue. The patient, her mother and her grand mother, but not her sister, had a heterozygote Y831C mutation.	Analysis by mispairing PCR showed the pres- ence of mutation Y831C in 57% of 87 controls.	(Barthelemy et al., 2002) PubMed
PEO, neuropathy, and parkinsonism	Found as a heterozyous mutation in a 49 y.o woman with parkinsonism, PEO, and mtDNA deletions. Her 59 y.o. brother was heterozygous for Y831C with overt parkinsonian features.	Mancuso 2004: Not seen in 120 control subjects	(Mancuso et al., 2004b)  PubMed
	The allelic discrimination technology proposed here for the identification of the mutation causing the Y831C substitution is amenable to high-throughput genotyping an thus is well suited to both extensive population studies and molecular diagnostics.	Stopinska 2006: present in the Polish population at a frequency of 2.25%.	(Stopinska et al., 2006) PubMed
Neutral polymorphism	Studied POLG1 in 140 UK patients with idiopathic Parkinson disease (PD) and 279 Italian patients with PD and compared them to a UK control group (n = 207) and an Italian control group (n = 285). Our observations do not support a role for common POLG1 gene	Tiangyou 2006: Found at the same frequency in age-matched controls.	(Tiangyou et al., 2006) PubMed
Neutral polymorphism	Found several amino acid substitutions, none of them associating with PD. These included a previously parkinsonism-associated POLG variant Y831C, found in one patient with PD, but also in five controls, suggesting that it is a neutral amino acid polymorph	The coding region of POLG1 was analyzed in 140 Finnish patients with PD and their 127 spouses as age- and ethnically matched controls.	(Luoma et al., 2007) PubMed
	Heterozygous, hypotonia, Autism, neuropathy, ataxia, hearing loss, short stature, muscle weakness, fatigue		(Wong et al., 2008) PubMed
mtDNA depletion	In trans w/ H1134R		(Taanman et al., 2008) PubMed
mtDNA deletions and seizures	Heterozygous mutation found in a 34 y.o. woman with seizures, opthalmoparesis, ptosis,, peripheral neuropathy…..	2 in 322 mitochondrial disease patients	(Woodbridge et al., 2012) PubMed
Muscle weakness	Heterozygous mutation found in a 46 y.o. woman with proximal weakness and myagia, and muscle twitches.	2 in 322 mitochondrial disease patients	(Woodbridge et al., 2012) PubMed
	Found in a Chinese population with Parkinsonism at an allelic frequency of 0.034	344 Chinese parkinson patients and 144 controls	(Gui et al., 2012) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: Y837C cDNA Position: 2510 a→g (exon 16)
Disease	Genetics	Frequency	Reference
Sensory axonal neuronopathy	Found in a 67 y.o. female and her 61 y.o. brother. Found in compound w/K601E, D122Y, Q1236H. Both patients have an ataxia, dysarthria, seizures, and sensory neuropathies.	Not found in 200 chromosomes controls	(Zabalza et al., 2014) PubMed
myopathy	Found as a heterozygous mutation in a 77 y.o. male with neck extensor muscles myopathy and mtDNA deletions		(Pozzo et al., 2017) PubMed
Ptosis	Found as a heterozygous mutation in a 61 y.o. female with ptosis, thyropathy, hearing loss, and mtDNA deletions		(Pozzo et al., 2017) PubMed

Amino Acid Substitution: A847T cDNA Position: 2539 g→a (exon 16)
Disease	Genetics	Frequency	Reference
PEO	Found in trans with T748Sin a 49 y.o. male with muscle weakness and sensory neuropathy. Patient has mtDNA deletions, COX negative muscle fibers, and ragged red fibers.	Not found in 100 controlsA847T	(Pozzo et al., 2017) PubMed

Amino Acid Substitution: G848S cDNA Position: 2542 g→a (exon 16)
Disease	Genetics	Frequency	Reference
PEO	Compound with T251I	Lamantea, 2002: absent in 100 control DNA samples	(Lamantea et al., 2002)  PubMed
Alpers	Found in compound w/A467T in a 6 mo. male w/	Ferrari et al., 2005 reported 1 in 9 (11.11%) children with a combination of progressive neurological and hepatic failure, with a heterozygous frequency of 1% of Italian controls.	(Ferrari et al., 2005)  PubMed
Alpers	Found as compound W748S/E1143G.		(Davidzon et al., 2005) PubMed
PEO	Compound with T251I and P587L in a 75 y.o. male		(Kollberg et al., 2005) PubMed
Alpers	Found as compound in Alpers with A467T and also in trans w/ W748 /E1143G.		(Nguyen et al., 2005) PubMed
Alpers	Found as compound in Alpers with A467T in a 6 mo. female	de Vries et al. , 2007 identified 1 (4.76%) children out of 21 with a POLG mutation that were known to have a mitochondrial disorder	(de Vries et al., 2007) PubMed
Alpers	Found as compound with A467T in a 6 mo. female w/ liver failure and encephalopathy	Not found in 250 control individuals	(Horvath et al., 2006) PubMed
Liver failure, encephalopathy, and epilepsy	Found as compound with A467T in a 3 mo. male w/ liver failure and encephalopathy	Not found in 200 control alleles	(Kollberg et al., 2006) PubMed
MELAS	Found w/ R627Q; heterozygous mutation; w/ mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.		(Deschauer et al., 2007) PubMed
Alpers	Found in trans with A467T, Q497H, W748S, and E1143G. Also found in trans w/ T251I-P587L.		(Wong et al., 2008) PubMed
Alpers	Found in trans w/W748S, and in a 2nd pt. in trans w/A467T.		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed
PEO and Ataxia	In trans w/ G746S and E1143G. Also found in trans w/ A467T.	Found in one child with a normal brain MRI.	(Stewart et al., 2009) PubMed
Leigh Syndrome	In trans w/R232H		(Taanman et al., 2008) PubMed
Alpers	In trans w/E1143G +W748S		(Taanman et al., 2008) PubMed
Alpers	Found in trans w/ Q497H, W748S, and E1143G.		(Brunetti-Pierri et al., 2008) PubMed
Myopathy and gastrointestinal obstruction	Found in trans w/ R227W with mtDNA depletion and Cox deficient muscle fibers		(Giordano et al., 2009) PubMed
mtDNA depletion	Found in trans with A467T		(Roels, et al., 2009) PubMed
Ptosis	ar, found in trans w/ T251I+P587L	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Cerebellar ataxia, sensory neuropathy, PEO, and dysphagia	Found with R627Q in a 35 yr. old patient		(Schulte et al., 2009) PubMed
Alpers	Found in trans with A467T		(Hasselmann et al., 2009) PubMed
Hepatocerebral - Alpers symptoms	Found in trans w/P1073L. Psychomotor delay, seizures, liver delay, and gastrointestinal dysmotility		(Kurt et al., 2010) PubMed
SANDO	Found sporadically w/T251I and P587L in a 80 yr. old male		(Weiss and Saneto, 2010) PubMed
Alpers	Found in trans with W748S and E1143G in a 11 mo. old with epilepsy and encephalopathy		(Isohanni et al., 2011) PubMed
Liver Diseases	Found in trans w/A467T in a 2 y.o. pt.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ A467T in an 8 y.o. pt. with seizures, muscle weakness, hypotonia, ataxia, hearing loss, and developmentally delayed.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ A467T in a 1 y.o. with seizures, elevated transaminases, and increased signal basal ganglia	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ W748S in a 5 y.o. pt. w/myclonic seizures, liver failure, and hypotonia	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ W748S in a 7 y.o. w/ seizures and cortical blindness	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans w/ W748S in a 3 y.o.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans w/ W748S in a 6 y.o. pt. with GI issues and irregular occipital lobe. Sibling died from VPA induced organ failure.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found as a homozygote in a 2 month old with seizures, an abnormal MRI, and abnormal respiratory enzymes.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Encephalopathy	Found in trans w/ R1096C in a 2 y.o. w/ hypotonia, ptosis, hepatic failure, and developmentally delayed.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Failure to thrive	Found in trans w/ P1073L in a 2 y.o. w/ hypotonia, and gastro-esophageal reflux.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found in trans w/ T25IL and P587L in an 80 y.o. w/ ptosis, PEO, peripheral neuropathy, and abnormal muscle histology.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ A143V in a 4 y.o. w/ hypotonia, encephalopathy, seizures, hepatic failure, and developmentally delayed	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ A143V in a 38 y.o. w/ ataxia, peripheral neuropathy, hearing loss, and seizures	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found in trans w/ c.3104+3a→t in a 63 y.o. w/ PEO, ptosis, hearing loss, muscle weakness and ragged red fibers	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ A143V in an 8 y.o. w/ seizures and an abnormal MRI	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans w/ A143V in a 37 y.o. symptoms not noted	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Alpers	Found in trans w/W748S in a 6 yr. 4 mo. with micro-vesicular fatty changes of the liver, myclonic seizures, and ataxia		(Hunter et al., 2011) PubMed
Alpers	found in trans w/W7484S in a 6 yr. 9 mo. with seizures, developmentally delayed, and ataxia.		(Hunter et al., 2011) PubMed
Alpers	Found in trans w/A467T in a 3 y.o. w/seizures, developmentally delayed, and ataxia		(Hunter et al., 2011) PubMed
Alpers	Found in trans w/A467T in a 11 mo. old w/seizures and developmentally delayed		(Hunter et al., 2011) PubMed
Alpers	Found in trans w/ A467T in a pediatric patient w/mitochondrial encephalomyopathy, seizures, ataxia, and ophthalmological involvement		(Sofou et al., 2012) PubMed
Alpers	Found in trans w/A467T in a 10 mo. old female with seizures and brain stem dysfunction. History revealed that a 24 y.o. cousin died from Alpers whom harbored a homozygous A467T variant.		(McCoy et al., 2011) PubMed
Alpers and Leigh's encephalopathy	Found in trans w/A467T in a 3.5 mo. old female with seizures and Alpers. Post mortem studies revealed Leigh's encephalopathy		(Scalais et al., 2012) PubMed
Optic atrophy	Also found in w/ c.3104+3A>T in a 63 y.o. male with exercise intolerance, hearing loss, ptosis, and parkinsonism.		(Milone et al., 2011) PubMed
Parkinsonism	Found in trans w/S1104C in a 59 y.o. male with mtDNA deletions and cerebellar ataxia		(Lax et al., 2012b) PubMed
PEO	Found in trans w/G746S in a 36 y.o. male with PEO, peripheral neuropathy, and ataxia		(Lax et al., 2012a) PubMed
PEO	Found in compound with T251I in a 45 yo female with mtDNA deletions	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
Encephalopathy	Found as a heterozygous mutation with A467T in a patient with epilepsy		(Tzoulis et al., 2013) PubMed
Encephalopathy	Found w/A467T in a 6 mo. child w/epilepsy and death at 6 mo.		(Tzoulis et al., 2014) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in trans w/T251I andP587L with PEO, muscle weakness, and cognitive impairment. Similar to SANDO, but no dysarthria.		(Bereau et al., 2016) PubMed
SANDO	Found in trans w/A467T with ataxia, sensory neuropathy, dysarthria, and PEO.		(Bereau et al., 2016) PubMed
Gait disturbance	Found w/R627Q in a 29 y.o. female with ataxia, speech abnormalities, and swallowing abnormalities		(Vogel et al., 2017) PubMed
mild ophthalmoparesis	Found in trans with R627Q in a 33 y.o. male with sensory ataxia and neuroathy		(Pozzo et al., 2017) PubMed
Severe cerebellar growth arrest in newborn	Homozygous G484S found.  Death of newborn at 5 days		(Inbar-Feignenberg et al., 2018) PubMed
Alpers	Found in trans with A467T in two babies		(Hayhurst et al., 2019) PubMed
Prenatally with fetal cerebellar growth arrest	Found two homozygous fetus. One was born and died at 5days and another one the pregnancy termintated at 22 weeks.		(Inbar-Feigenberg et al., 2018) PubMed
MDS	Found as heterozygous in trans with W748S with peripheral neuropathy, transient hepatic dysfunction, and progressive encephalopathy with ataxia and psychiatric symptoms		(Blazquez-Bermejo et al., 2019) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: T849X cDNA Position: 2544 (insertion of c with fs868X) (exon 16)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans with A467T and in cis with Q1236H		(Wong et al., 2008) PubMed

Amino Acid Substitution: T851A cDNA Position: 2551 a→g (exon 16)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans w/R1047W.	Not found in over 100 control alleles	(Wiltshire et al., 2008) PubMed
Alpers	Found in trans w/H277L.		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed
Opthmalplegia and seizures	Found in trans w/P163S in a 21 y.o. female with peripheral neuropathy, seizures, dysarthria and bilateral ptosis	2 in 322 mitochondrial disease patients	(Woodbridge et al., 2012) PubMed
Opthmalplegia and peripheral neuropathy	Found in trans w/N468D in a 49 y.o. female with ptosis, lower limb weakness, sensory ataxia, gastrointestinal symptoms, and peripheral neuropathy	2 in 322 mitochondrial disease patients	(Woodbridge et al., 2012) PubMed

Amino Acid Substitution: R852C cDNA Position: 2554 c→t (exon 16)
Disease	Genetics	Frequency	Reference
Alpers	Compound with A467T	Not found in 300 control chromosomes	(Nguyen et al., 2006) PubMed
Ataxia Neuropathy	Found in trans w/ G11D-R627Q		(Wong et al., 2008) PubMed
Alpers	Found in cis w/G11D and in trans w/W748S, and in a 2nd pt. found in cis w/G11D and in trans w/A467T.		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed
Alpers	Found in cis w/G11D and in trans w/ A467T. In a 2nd pt., found in cis w/G11D and in trans w/ W748S and E1143G.		(Stewart et al., 2009) PubMed
Leigh Syndrome	Found in cis with G11D and in trans with W748S		(Naess, et al., 2009) PubMed
Multiple system atrophy	Found with G11D in a 58 y.o. female with progressive cerebellar atrophy. Pt. had mtDNA deletions and mtDNA depletion.		(Mehta et al., 2011) PubMed
Seizures and liver failure	Found in trans w/ A467T and in cis w/ G11D in a 8 mo. w/ seizures, liver failure, and lactic acidosis.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Encephalopathy	Found in cis w/ G11D and in trans w/ R627Q in a 25 y.o. w/ dementia, encephalopathy, and stroke.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Alpers	Found in trans w/A467T in a 5 y.o. w/seizures, ataxia, and developmentally delayed		(Hunter et al., 2011) PubMed
Alpers	Found in trans w/A467T in a 21 mo. old female with blindness, anarthria, hypotonia, and epilepsy		(McCoy et al., 2011) PubMed
Alpers and PEO	Found in trans with W748S in a pediatric female patient with hypotonia, developmental delay, ataxia, and seizures		(Vasta et al., 2012) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in cis w/P587L and T251I in a 50 y.o. with PEO, muscle weakness, and polyneuropathy. Similar to SANDO, but no dysarthria.		(Bereau et al., 2016) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: R852H cDNA Position: 2555 g→a (exon 16)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans w/ W748S in a 3 y.o. w/ Alpers	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: R853W cDNA Position: 2557 c→t (exon 16)
Disease	Genetics	Frequency	Reference
PEO with ptosis	Found as compound in trans with P587L Parkinsonism in compound in trans with G737R	24 patients diagnosed with mitochondrial disease and having multiple mtDNA deletions compared to 100 controls in a Spanish population.	(Gonzalez - Vioque et al., 2006) PubMed
Parkinsonism			(Davidzon et al., 2006) PubMed
Parkinsonism	Found in trans with G737R in a 32 y.o. female with early signs of Parkinsonism and COX negative muscle fibers. Levodopa-responsive.		(Rempe et al., 2016) PubMed

Amino Acid Substitution: R853Q cDNA Position: 2558 g→a (exon 16)
Disease	Genetics	Frequency	Reference
Myocerebrohepatopathy	In trans with T251I-P587L		(Wong et al., 2008) PubMed

Amino Acid Substitution: V855L cDNA Position: 2563 g→t (exon 16)
Disease	Genetics	Frequency	Reference
Seizures	Found in trans w/ G737R in an 8 mo. w/ seizures, liver failure, and developmentally delayed	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: V855A cDNA Position: 2564 t→c (exon 16)
Disease	Genetics	Frequency	Reference
	Heterozygous with muscle weakness.		(Wong et al., 2008) PubMed

Amino Acid Substitution: A862T cDNA Position: 2584 g→a (exon 16)
Disease	Genetics	Frequency	Reference
Ataxia Neuropathy	Compound heterozygous with R964C		(Wong et al., 2008) PubMed
PEO with ataxia	Found in trans w/R1047W in a 61 y.o. with PEO, ataxia, and mtDNA deletions		(Stewart et al., 2009) PubMed
Cerebellar ataxia, neuropathy, epilepsy, and restless leg syndrome	Found heterozygous with R964C in 2 siblings that died in their early 20's		(Stricker et al., 2009) PubMed
Alpers-like	Found in trans with R1081Q in a 7 y.o. male with Alpers-like symptoms. Affected sibling.		(Ferreira et al., 2011) PubMed
Alpers-like	Found in trans with R1081Q in a 4 y.o. male with Alpers-like symptoms. Affected sibling.		(Ferreira et al., 2011) PubMed
Myelopathy,myopathy, peripheral neuropathy and subcortical grey matter degeneration	Found in trans w/H277L in a 66 y.o. female with mtDNA deletions and subcortical grey matter degeneration		(McKelvie et al., 2012) PubMed
PEO	Found in trans w/ R1047W in a 61 y.o. female with PEO, ptosis, peripheral neuropathy, ataxia, and dysarthria.		(Lax et al., 2012a) PubMed

Amino Acid Substitution: N864S cDNA Position: 2591 a→g (exon 16)
Disease	Genetics	Frequency	Reference
PEO	Found as compound with T251I-P587L	Not found in 280 control chromosomes	(Van Goethem et al., 2003c) PubMed
Epilepsy	Found as heterozygous in trans with A1217P in a 3-year-old girl presented with severe epilepsy in the context of Borrelia infection.		(Gaudó et al., 2020) PubMed

Amino Acid Substitution: IVS16-10 c>t cDNA Position: IVS16-10 c>t (exon 16)
Disease	Genetics	Frequency	Reference
Cerebellar ataxia, sensory neuropathy, and dysphagia	Homozygous. Found in a 60 yr. old patient		(Schulte et al., 2009) PubMed

Amino Acid Substitution: R869Q cDNA Position: 2606 g→a (exon 17)
Disease	Genetics	Frequency	Reference
Myopathy w/ neurogenic atrophy; sensomotor axonal polyneuropathy, ataxia, and ptosis	Autosomal recessive, found in a 32 yr. old pt.	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed
PEO	Found in trans w/ K319E in a 44 y.o. w/ PEO, ataxia, neuropathy, and muscle weakness	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
SANDO	Found in trans w/P587L and w/T251I in a 34 y.o. female with ataxia, ptosis, diabetes and mtDNA deletions.		(Hanisch et al., 2014) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed
Hepaticencephalopathy, Alpers-Huttenlocher	Found as compound heterzygous in trans with G1051R in a one year old boy. Death at 1.8 years old.		(Dai et al., 2019) PubMed

Amino Acid Substitution: R869X cDNA Position: 2605 a→t (exon 17)
Disease	Genetics	Frequency	Reference
Hepatocerebral MDS	Found in trans with W748S. This infant died at 30 months and had epileptic encephalopathy and multiorgan deterioration.		Pronicki et al., 2018) PubMed

Amino Acid Substitution: E873X cDNA Position: 2617 g→t (exon 17)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans with A467T and under goes nonsense-mediated decay for mono-allelic expression of POLG	Not found in 40 alleles from non-Alpers mitochondrial disease patients	(Chan et al., 2005b) PubMed
Alpers	Found in trans with A467T	Not found in 40 alleles from non-Alpers mitochondrial disease patients	(Naviaux and Nguyen, 2004) PubMed
Alpers	Found in trans w/A467 in and 18 mo. old male w/ mtDNA depletion		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed

Amino Acid Substitution: L874M cDNA Position: 2620 t→a (exon 17)
Disease	Genetics	Frequency	Reference
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: Q879H cDNA Position: 2637 g→t (exon 17)
Disease	Genetics	Frequency	Reference
Liver failure and encephalopathy	Found in cis with E1143G and in trans with A467T-T885S	Not found in 250 control individuals	(Horvath et al., 2006) PubMed
Alpers w/ valproate-induced hepatic failure	Found in cis with E1143G and in trans with A467T-T885S in a 2 y.o. male		(McFarland et al., 2009) PubMed

Amino Acid Substitution: Q879R cDNA Position: 2636 a→g (exon 17)
Disease	Genetics	Frequency	Reference
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: P881L cDNA Position: 2642 c→t (exon 17)
Disease	Genetics	Frequency	Reference
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: T885S cDNA Position: 2653 a→t (exon 17)
Disease	Genetics	Frequency	Reference
Alpers	Found in cis with A467T and in trans with Q879H-E1143G	Not found in 250 control individuals	(Horvath et al., 2006) PubMed
Alpers w/ valproate-induced hepatic failure	Found in cis with A467T, and in trans w/Q879H and E1143G		(McFarland et al., 2008) PubMed

Amino Acid Substitution: L886P cDNA Position: 2657 t→c (exon 17)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans w/ A467T		(Wong et al., 2008) PubMed

Amino Acid Substitution: G888S cDNA Position: 2662 g→a (exon 17)
Disease	Genetics	Frequency	Reference
Alpers	Compound heterozygous with L83P in 10 yr. old		(Bao et al., 2007) (Wong et al., 2008) PubMed

Amino Acid Substitution: G888D cDNA Position: 2663 g→a (exon 17)
Disease	Genetics	Frequency	Reference
Seizures and liver failure	Found in trans w/ W748S in a 2 y.o. w/ seizures, hepatic failure, ketosis and abnormal MRI	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Alpers	Found in trans w/L304R in a patient showing psychomotor retardation, epileptic encephalopathy, progressive cerebral atrophy, and altered liver enzymes.	1 of 52 pediatric patients suspected to have mitochondrial DNA depletion syndrome	(Navarro-Sastre et al., 2012) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: A889T cDNA Position: 2665 g→a (exon 17)
Disease	Genetics	Frequency	Reference
PEO	Sporadic / unknown Compound with R579W Compound with E1143G	Filosto, 2003: not detected in 120 healthy control alleles	(Filosto et al., 2003) PubMed
PEO	Sporadic / unknown Compound with R579W Compound with E1143G		(Hisama et al., 2005) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: D890A cDNA Position: 2669 a→c (exon 17)
Disease	Genetics	Frequency	Reference
MNGIE-like	Found as a heterozygous mutation in a 20 y.o. male w/ progressive gastrointestinal dysmotility, cachexia, PEO, and peripheral neuropathy.		(Parsun and Koeberl, 2014) PubMed

Amino Acid Substitution: D892GfsX39 cDNA Position: 2675 ins g (exon 17)
Disease	Genetics	Frequency	Reference
	Found in trans w/ W748S in a 9 mo. old pt. with a deceased sibling.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: E895G cDNA Position: 2684 a→g (exon 17)
Disease	Genetics	Frequency	Reference
Myopathic MDS	Found in one newborn with floppiness and 20% liver mtDNA depletion, heterozygous		(Spinazzola et al., 2009) PubMed

Amino Acid Substitution: I898T cDNA Position: 2693 t→c (exon 17)
Disease	Genetics	Frequency	Reference
Early-onset Parkinson's disease	Found as compound heterozygous in trans with S998L in a 29-year-old female presented with levodopa-responsive parkinsonism, external ophthalmoplegia and optic atrophy.		(Ma et al., 2020) PubMed

Amino Acid Substitution: F907I cDNA Position: 2719 t→a (exon 17 or 18)
Disease	Genetics	Frequency	Reference
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: T914A cDNA Position: 2740 a→g (exon 18)
Disease	Genetics	Frequency	Reference
Multiple Sclerosis-like illness	Found as a heterozygous mutation w/Y452C in a 56 yr. old. Pt. first diagnosed w/ optic neuritis and MS 19 yrs. earlier. Currently has ragged-red muscle fibers, ptosis, myopathies, and mtDNA deletions.		(Echaniz-Laguana et al., 2010) PubMed
Alpers	Found in trans with A467T in a 9 mo. old with epilepsy and encephalopathy	7 of 136 mitochondrial disease Finnish children, and screened against 370 control DNA samples	(Isohanni et al., 2011) PubMed

Amino Acid Substitution: T914P cDNA Position: 2740 a→c (exon 18)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans with A467T.	Not found in 300 control chromosomes	(Nguyen et al., 2006)  PubMed
Encephalopathy	Found in trans with A467T in an 8 y.o. male w/encephalopathy and myoclonus .	Not found in 250 control individuals	(Horvath et al., 2006)  PubMed
Alpers	Found in trans with A467T in a 7 mo. female w/ Alpers	Not found in 300 healthy French control chromosomes	(Naimi et al., 2006) PubMed
Alpers	Found in trans w/ A467T		(Wong et al., 2008) PubMed
adPEO	Heterozygous, Ptosis, exercise intolerance, fatigue, ragged red fibers		(Wong et al., 2008) PubMed
Alpers	Found in trans w/R1096C, and in a 2nd pt. found in trans w/R627W. Also found in trans w/A467T in 2 other pts. Found in 2 additional pts. in trans w/W748S.		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed
Alpers	In trans w/ A467T		(Taanman et al., 2008) PubMed
Epilepsy, myoclonic, and developmental delay	ar, Found as a compound heterozygous mutation w/ A467T	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Epilepsy	Found heterozygous with A467T in a 10 mo. old male with myoclonic seizures and jerks, and developmental regression.		(Dhamija et al., 2011) PubMed
Alpers	Found in trans with E1143G and W748S in a 2.5 y.o. with epilepsy and encephalopathy	7 of 136 mitochondrial disease Finnish children, and screened against 370 control DNA samples	(Isohanni et al., 2011) PubMed
Seizures	Found in trans w/ A467T in a 3 y.o. w/ seizures, hypotonia, encephalopathy, and developmentally delayed	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ W748S in a 5 y.o. w/ seizures	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ A467T in a 5 y.o. w/ seizures, hearing loss, and developmentally delayed.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ W748S in an 8 mo. w/ seizures, hypotonia, abnormal MRI, and developmentally delayed.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ A467T in a 9 mo. w/ seizures, hypotonia, and developmentally delayed	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures and liver failure	Found in trans w/ A467T in a 4 y.o. with liver failure, seizures, and failure to thrive	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ A467T in an 8 mo. w/ seizures, respiratory failure, and an abnormal MRI	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
MSCAE	Found in trans w/ W748S in a 15 y.o. female with mitochondrial spinocerebellar ataxia and epilepsy.		(Hinnell et al., 2012) PubMed
Alpers	Found in compound with A467T in a 15 month female with mtDNA depletion	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
Epilepsy	Found in compound with W748S in a 6 yo male with epilepsy and hepatic cholestasis and cytolysis, and mtDNA deletions	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
PEO	Found in compound with the intronic mutation C3104+3A>T in a 37 y.o. male with PEO. Myopathy, dysphagia, and muscle weakness developed by age 55. Pt.'s older brother was diagnosed with PEO at age 65, and pt.'s adult daughters are not affected. Pt. had C		(Roos et al., 2013) PubMed
Alpers	Found in trans with A467T in one baby		(Hayhurst et al., 2019) PubMed
Myopathy, PEO, and Ptosis	Found as compound heterozygous in trans with F197S in a 69 year-old man with slowly progressive bilateral ptosis and severely reduced horizontal and vertical gaze.		( Hedberg-Oldfors et al., 2020) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: W918R cDNA Position: 2752 t→c(exon 18)
Disease	Genetics	Frequency	Reference
PEO with Parkinsonism	ar, Compound (in trans) heterozygous with M430L	Absent in 200 control alleles	(Invernizzi et al., 2008) PubMed
PEO	Found in trans with M430L in a 42 y.o. male with PEO and mtDNA		(Ferreira et al., 2011) PubMed

Amino Acid Substitution: M919T cDNA Position: 2755 a→t (exon 18)
Disease	Genetics	Frequency	Reference
PEO	Found in compound w/A467T in a 23 y.o. female patient w/ chronic intestinal pseudo-obstruction, PEO, and ataxia.	In 5 out of 80 patients w/ chronic intestinal pseudo-obstruction	(Amiot et al., 2009) PubMed
SANDO	Found in trans with Y986D in a 34 y.o. with PEO, ataxia, sensory neuropathy, dysarthria, depression, and migraines.		(Bereau et al., 2016) PubMed

Amino Acid Substitution: G923D cDNA Position: 2768 g→a (exon 18)
Disease	Genetics	Frequency	Reference
PEO	Found as a homozygous mutation in 2 patients w/ mtDNA deletions. Also found as a heterozygous mutation with little or no symptoms.	Lamantea, 2002: absent in 100 control DNA samples	(Lamantea et al., 2002) PubMed
PEO	ad PEO. Studied the pathological and biochemical consequences of several PEO mutations by modeling the amino acid changes and structure pol _. In order to correlate mutation and disease severity.		(Graziewicz et al., 2004) PubMed
PEO	Demonstrate that S. cerevisiae provides a useful in vivo system for quickly evaluating the biological consequences of identified, or suspected, PEO mutation loci.		(Stuart et al., 2006) PubMed

Amino Acid Substitution: G923R cDNA Position: 2767 c→g (exon 18)
Disease	Genetics	Frequency	Reference
	Reference # rs60636456		PubMed

Amino Acid Substitution: K925R fs42X cDNA Position: 2772_2773 delG
Disease	Genetics	Frequency	Reference
Prematurity, epilepsy, deafness, retinitis pigmentosa, hemiparesis, and liver failure	Found in trans w/A467T.	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed

Amino Acid Substitution: D930N cDNA Position: 2788 g→a (exon 18)
Disease	Genetics	Frequency	Reference
Alpers	Infantile Alpers w/ bilateral lesions of thalami. Hepatocerebral MDS patient, Found in trans w/ W748S.		(Spinazzola et al., 2009) PubMed

Amino Acid Substitution: H932Y cDNA Position: 2794 c→t (exon 18)
Disease	Genetics	Frequency	Reference
PEO and mtDNA deletions	Found in compound w/T251I/ P587L in1 pt. The study includes 31 mitochondrial myopathy patients w/ mtDNA deletions.	Di Fonzo 2003: Not found in 100 DNA samples from healthy Italians	(Di Fonzo et al., 2003) PubMed
PEO	Found in compound with G1051R in 2 family members PEO	not seen in 120 control subjects.	(Mancuso et al., 2004a) PubMed
	Isolated distal myopathy of the upper limbs w/ mtDNA depletion		(Giordano et al., 2010) PubMed
PEO	Found in trans w/ P587L and T251I in a 31 y.o. w/ neuropathy, PEO, ptosis, and COX deficiency.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Peripheral Neuropathy	Found in trans w/ T251I and P587L in a 40 y.o. w/ peripheral neuropathy, ptosis, and muscle weakness.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Neuropathy w/ cataracts and glaucome	Found in trans with P648R in a 1 y.o. male with uppper and lower limb distal neuromyopathy with ragged red fiberes, cataracts. Later developed strabismus, ptosis, glaucoma, and muscle weakness.		(Castiglioni et al., 2018) PubMed

Amino Acid Substitution: S933R cDNA Position: 2799 t→g (exon 18)
Disease	Genetics	Frequency	Reference
PEO	Found in trans w/ Q1214LX in a 60 y.o. w/ PEO, dementia, myopathy, and abnormal muscle histology	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ A957V in a 3 mo. w/ seizures, hypotonia, and developmentally delayed	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: R943C cDNA Position: 2827 c→t (exon 18)
Disease	Genetics	Frequency	Reference
Myocerebrohepatopathy	In cis w/ E1143G and in trans w/G737R		(Wong et al., 2008) PubMed
PEO and Parkinsonism	Found in trans w/H227L in a 78 y.o. Japanese malewith parkinsonism. Also found as a heterozygous mutation in a second unrelated 68 y.o. malewith PEO.	not found in 50 ethnically matched controls	(Sato et al., 2011) PubMed
Neuropathy w/ cataracts and glaucome	Found in trans with T25lI/P57L in an 8 mo. female with uppper and lower limb distal neuromyopathy with ragged red fiberes, cataracts. Later developed ophthalmoparesis, glaucoma, and muscle wasting.		(Castiglioni et al., 2018) PubMed
Neuropathy w/ cataracts and glaucome	Found in trans with T251I/P587L in an 24 mo. female with uppper and lower limb distal neuromyopathy with ragged red fiberes, cataracts. Later developed ophthalmoparesis, glaucoma, and muscle wasting.		(Castiglioni et al., 2018) PubMed

Amino Acid Substitution: R943H cDNA Position: 2828 g→a (exon 18)
Disease	Genetics	Frequency	Reference
PEO	ad PEO. Found in 2 siblings as a homozygous mutation	Lamantea, 2002: Not found in a control group of 100 DNA samples from unrelated Italians	(Lamantea et al., 2002) PubMed
PEO	ad PEO. Studied the pathological and biochemical consequences of several PEO mutations by modeling the amino acid changes and structure pol _. In order to correlate mutation and disease severity.		(Graziewicz et al., 2004) PubMed
PEO	Demonstrate that S. cerevisiae provides a useful in vivo system for quickly evaluating the biological consequences of identified, or suspected, PEO mutation loci.		(Stuart et al., 2006) PubMed
Premature ovarian failure	Ad, and premature ovarian failure	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed
PEO and Parkinsonism	Found as a heterozygous mutation in a 63 y.o. male with PEO, resting tremors, dysarthria, and poly neuropathy, fatigue, hearing lass, and Parkinsonism		(Brandon et al., 2013) PubMed

Amino Acid Substitution: H945L cDNA Position: 2834 a→t (exon 18)
Disease	Genetics	Frequency	Reference
PEO and Parkinsonism	Found as a heterozygous mutation in an 80 y.o. female with PEO, ptosis, neuropathy, cognitive decline, ragged red fibers, mtDNA deletions, and striatal dopamine deficiency.		(Delgado-Alvarado et al., 2015) PubMed

Amino Acid Substitution: K947R cDNA Position: 2840 g→a (exon 18)
Disease	Genetics	Frequency	Reference
PEO and ovarian failure	Compound heterozygote found w/ expansion of a polyQ (18Q) stretch.		(Baruffini et al., 2011) PubMed

Amino Acid Substitution: Y951N cDNA Position: 2851 t→a (exon 18)
Disease	Genetics	Frequency	Reference
Peripheral Neuropathy	Found as a heterozygous mutation in 22 y.o. w/ peripheral neuropathy	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
3-methyl glutaconic aciduria	Found as a heterozygous mutation in a 23 y.o. female with progressive muscle weakness, cataracts, and ovarian dysgenesis		(Bekheirnia et al., 2012) PubMed

Amino Acid Substitution: R953C cDNA Position: 2857 c→t (exon 18)
Disease	Genetics	Frequency	Reference
PEO	ad	Luoma, 2004: None noted in screening of 1640 healthy Finnish control chromosomes.	(Luoma et al., 2004) PubMed
	Reference # rs11546842		PubMed
PEO	Found in trans w/ W748S in a 51 y.o. w/ peripheral neuropathy, ptosis, hypotonia, ataxia, and seizures.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Autosomal recessive PEO, found as a homozygous mutation in 3 affected siblings and heterozygous in 2 asymptomatic siblings from the same family. One unaffected sibling had no POLG mutations. Symptoms started in early 20's of the 3 affected siblings whic		(Gurgel-Giannetti et al., 2012) PubMed
MNGIE-like	Found in compound with W748S in a 50y.o. male with cognitive impairment, muscle weakness, diarrhea, vomiting, ptosis, and opthalmoparesis.		(Tang et al., 2012) PubMed
MItochondrial toxicity	Found as a heterozygous mutation in a HIV positive patient with mitochondrial toxicity		(Li et al., 2016) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: R953P cDNA Position: 2858 g→c (exon 18)
Disease	Genetics	Frequency	Reference
Hepaticencephalopathy, Alpers-Huttenlocher	Found as compound heterzygous in trans with P765L in a two year old girl.		(Dai et al., 2019) PubMed

Amino Acid Substitution: Y955C cDNA Position: 2864 a→g (exon 18)
Disease	Genetics	Frequency	Reference
PEO	ad PEO in a family w/ mtDNA deletions	absent in 432 control chromosomes	(Van Goethem et al., 2001) PubMed
PEO	Found as a heterozygous mutation in 3 Belgian families w/ PEO	Lamantea, 2002: Not found in a control group of 100 DNA samples from unrelated Italians	(Lamantea et al., 2002) PubMed
PEO	ad PEO. Studied the pathological and biochemical consequences of several PEO mutations by modeling the amino acid changes and structure pol _. In order to correlate mutation and disease severity.		(Graziewicz et al., 2004) PubMed
Parkinsonism Premature ovarian failure Alzheimer's disease	Most severe autosomal dominant mutation in POLG, drastically lowers polymerase catalysis, promotes stalling and errors in replication.	Luoma, 2004: None noted in screening of 1640 healthy Finnish control chromosomes.	( Luoma et al., 2004) PubMed
PEO and Premature ovarian failure	Found as a heterozygous and homozygous mutation in 3 generations of women in the same family with Premature ovarian failure and PEO. Also found in trans w/Q1236H.		(Pagnamenta et al., 2006) PubMed
PEO	Studied recombinant protein and found that the Y955C POLG enzyme cause error-prone DNA synthesis		(Ponamarev et al., 2002) PubMed
PEO	Demonstrate that S. cerevisiae provides a useful in vivo system for quickly evaluating the biological consequences of identified, or suspected, PEO mutation loci.		(Stuart et al., 2006) PubMed
PEO	Studied the yeast homologue that had mtDNA depletion and deletions with altered dNTP pools		(Baruffini et al., 2006) PubMed
PEO	Studied 4 pts. with adPEO and that were heterozygous for Y955C which revealed a low instance of mtDNA point mutations.		(Kollberg et al., 2005) PubMed
PEO	Y955C POLG was targeted transgenically to the murine heart. The mice had cardiomyopathy and mtDNA depletion.		(Lewis et al., 2007) PubMed
PEO/Alzheimer's	Myopathy, COX deficient muscle fibers, and mtDNA depletion found in 2 siblings who developed Alzheimer's and thought to have aged prematurely.		(Melberg et al., 2005) PubMed
	Found as a heterozygous mutation w/ hearing loss, failure to thrive, generalized ETC complex deficiency		(Wong et al., 2008) PubMed
PEO	Found in cis w/ G517V in a 47 y.o. w/ PEO, ptosis, myopathy, and neuropathy	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found as a heterozygous mutation in a 45 y.o. w/ myopathy and PEO	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in a Chinese population with Parkinsonism at an allelic frequency of 0.816	344 Chinese parkinson patients and 144 controls	(Gui et al., 2012) PubMed
PEO and Parkinsonism	Found as heterozygous mutations in siblings in Japan		(Mukai et al., 2013) PubMed
PEO and infertility	Found as a heterozygous dominate mutation in a patient with PEO and ovarian failure with mtDNA deletions,and COX negative muscle fibers		(Siibak et al., 2017) PubMed
Ptosis and ophthalmoparesis	Found as a heterozygous mutation in a 45 y.o. female with ataxia		(Vogel et al., 2017) PubMed
Ptosis and ophthalmoparesis	Found as a heterozygous mutation in a 29 y.o. male with a speech abnormalities, and swallowing abnormalities		(Vogel et al., 2017) PubMed
Ptosis and ophthalmoparesis	Found as a heterozygous mutation in a 26 y.o. male with a speech abnormalities, and swallowing abnormalities		(Vogel et al., 2017) PubMed
PEO and Parkinsonism	Found as a heterozygous mutation in a 59 y.o. female with parkinsonism, diabetes, hearing loss, and cortical atrophy. Patient was positive for mtDNA deletions.		(Pozzo et al., 2017) PubMed
Ptosis and myopathy	Found as heterozygous with late-onset bilateral ptosis and incomplete external ophthalmoparesis associated with an intense muscle fatigue, low physical endurance, and myalgia after low intensity exercise.		(Blazquez-Bermejo et al., 2019) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: Y955H cDNA Position: 2863 t→c (exon 18)
Disease	Genetics	Frequency	Reference
Progressive multi-systemic disorder	Found in cis w/Q1236H in an 8 month old with weight loss, hearing loss, myopathy, liver failure, decreased ATP production, COX negative muscle fibers, and ragged red fibers.		(Siibak et al., 2017) PubMed

Amino Acid Substitution: A957S cDNA Position: 2869 g→t (exon 18)
Disease	Genetics	Frequency	Reference
PEO	Found as both a heterozygous and as a homozygous mutation in one individual in two Sicilian families.	Lamantea, 2002: Not found in a control group of 100 DNA samples from unrelated Italians	(Lamantea et al., 2002) PubMed
PEO	ad PEO. Studied the pathological and biochemical consequences of several PEO mutations by modeling the amino acid changes and structure pol _. In order to correlate mutation and disease severity.		(Graziewicz et al., 2004) PubMed
PEO	Demonstrate that S. cerevisiae provides a useful in vivo system for quickly evaluating the biological consequences of identified, or suspected, PEO mutation loci.		(Stuart et al., 2006) PubMed

Amino Acid Substitution: A957P cDNA Position: 2869 g→c (exon 18)
Disease	Genetics	Frequency	Reference
Alpers	Found in compound w/A467T in a 8 mo. old male w/ multiple complex deficiencies	de Vries et al. , 2007 identified 1 (4.76%) children out of 21 with a POLG mutation that were known to have a mitochondrial disorder	(de Vries et al., 2007) PubMed
Alpers	Found in compound w/A467T in a 6 mo. old w/ infantile hepatocereberal syndrome.	Ferrari, 2005: absent in 200 consecutive control individuals from Northern continental Europe as well as 350 Italian controls	(Ferrari et al., 2005) PubMed
Epilepsy, liver failure, occipital strokes, and growth retardation	ar, found as a compound heterozygous mutation w/ A467T	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed

Amino Acid Substitution: A957V cDNA Position: 2870 c→t (exon 18)
Disease	Genetics	Frequency	Reference
Seizures	Found in trans w/ C1077G in a 2 y.o. w/ seizures, encephalopathy, and hypotonia	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
	Found in trans w/ G737R in a 4 mo. Symptoms not noted	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found in trans w/ S933R in a 3 mo. w/ seizures, hypotonia, and developmentally delayed	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Myocerebrohepatopathy spectrum disorder	Found in compound w/ I1185T in an 8 mo. Japanese female. Hypotonia, failure to thrive, hepatomegaly, and developmental regression.	Hetero compound not found in 1000 Genome Project, ESP6500 data base, nor HGVD	(Montassir, et al., 2014) PubMed

Amino Acid Substitution: F961S cDNA Position: 2882 t → c (exon 18)
Disease	Genetics	Frequency	Reference
PEO	ad PEO		(Adachi et al., 2002) PubMed

Amino Acid Substitution: A962T cDNA Position: 2884 g→a (exon 18)
Disease	Genetics	Frequency	Reference
Ataxia	Found in trans w/ R964C in a 14 y.o. w/ ataxia, muscle weakness, and central hypoventilation	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: R964C cDNA Position: 2890 c → t (exon 18)
Disease	Genetics	Frequency	Reference
Mitochondrial toxicity susceptibility to NRTIs	Found in a HIV1 patient with hyperlactatemia following 1 yr. of d4T and 3TC anti-viral treatment	Not found in 26 Thai HIV-1-infected individuals, or 110 healthy volunteers	(Yamanaka et al., 2007) PubMed
Ataxia Neuropathy	Found in trans w/ A862T, and found as a heterozygous mutation w/ ataxia and hypotonia		(Wong et al., 2008) PubMed
Cerebellar ataxia, neuropathy, epilepsy, and restless leg syndrome	Found heterozygous with A862T in 2 siblings that died in their early 20’s		(Stricker et al., 2009) PubMed
Ataxia	Found in trans w/ A962T in a 14 y.o. w/ ataxia, muscle weakness, and central hypoventilation	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
PEO	Found in trans w/Q53-Q55 duplicate in an 8 y.o. male with recessive ataxia, PEO, and hyoptonia		Ohba et al., 2013 PubMed
Ovarian dysfunction	Found one homozygous female with irregular menstrual cycles and abnormal oocytes.		(Chen et al., 2018) PubMed
Young onset Parkinson's disease	Found as heterozygous in cis with GBA L444P in a 59-year-old male presenting with right hand tremor at the age of 39 years, followed by slow movement, rigidity, and postural instability.		(Hsieh et al., 2019) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: L965X cDNA Position: 2894 t→g (exon 18)
Disease	Genetics	Frequency	Reference
Myoclonus epilepsy	ar, found in cis with E1143G and in trans with R627Q-Q1236H w/ liver dysfunction and encephalopathy	Not found in 250 control individuals	(Horvath et al., 2006) PubMed

Amino Acid Substitution: L966R cDNA Position: 2897 t→g (exon 18)
Disease	Genetics	Frequency	Reference
Alpers	Compound with A467T	Not found in 300 control chromosomes	(Nguyen et al., 2006) PubMed
Alpers	In trans w/A467T.		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed
Alpers	Found in trans w/A467T in a 1 y.o. w/ seizures and developmentally delayed		(Hunter et al., 2011) PubMed
Alpers	Found in trans w/A467T in a 1 y.o. w/ seizures and developmentally delayed		(Hunter et al., 2011) PubMed
Alpers	Found in trans w/A467T in a 17 mo. old male with seizures and encephalopathy		(McCoy et al., 2011) PubMed

Amino Acid Substitution: G975stop cDNA Position: 2923 c→t (exon 18)
Disease	Genetics	Frequency	Reference
Seizures	Found as a heterozygous mutation in a 6 yo female with dystonia, psychomotor delay, and seizures	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed

Amino Acid Substitution: Y986D cDNA Position: 2956 t→g (exon 18)
Disease	Genetics	Frequency	Reference
SANDO	Found in trans with M919T in a 34 y.o. with PEO, ataxia, sensory neuropathy, dysarthria, depression, and migraines.		(Bereau et al., 2016) PubMed

Amino Acid Substitution: T989dup(CAA/) cDNA Position: 2963_2975 ins CAA (exon 18)
Disease	Genetics	Frequency	Reference
PEO	Found in trans with T251I and P587L in a 36 y.o. female with cornieal edema and muscle weakness. One brother affected and has both variants and one unaffected sister with no mutations.	Not found in 100 random controls	(Pozzo et al., 2017) PubMed

Amino Acid Substitution: S998W cDNA Position: 2993 c→g (exon 19)
Disease	Genetics	Frequency	Reference
	Reference # rs79840247		PubMed

Amino Acid Substitution: S998L cDNA Position: 2993 c→t (exon 19)
Disease	Genetics	Frequency	Reference
PEO	Found as a compound heterozygote with D1184H in a 64 y.o. female with PEO, bilateral ptosis, and encephalopathy.		(Martikainen et al.,) PubMed
Early-onset Parkinson's disease	Found as compound heterozygous in trans with I898T in a 29-year-old female presented with levodopa-responsive parkinsonism, external ophthalmoplegia and optic atrophy.		(Ma et al., 2020) PubMed

Amino Acid Substitution: W1020X cDNA Position: 3057 g→a (exon 19)
Disease	Genetics	Frequency	Reference
Alpers	Compound with A467T		(Nguyen et al., 2005) PubMed

Amino Acid Substitution: Q1024X cDNA Position: 3067 c→t (exon 19)
Disease	Genetics	Frequency	Reference
Seizures	Found in trans w/ A467T in a 2 y.o. w/seizures, hearing loss, and hemiparesis	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: A1033V cDNA Position: 3098 c→t (exon 19)
Disease	Genetics	Frequency	Reference
Lethal MDS	Found one heterzygous female neonate in trans with R227Q. The baby died at the age of 5 months.		(AlJabri et al., 2018) PubMed

Amino Acid Substitution: c. 3104 +3a→t cDNA Position: 3104 +3a→t (splice variant between ex. 19 and 20)
Disease	Genetics	Frequency	Reference
PEO	Found in trans w/ F749S in a 66 y.o. w/ PEO, ptosis, myopathy, and muscle weakness	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Optic atrophy	Found in trans w/F749S in a 65 y.o. male with ptosis, dysphagia, exercise induced myalgia, limb weakness, and diabetes. Also found in trans w/ G8484S in a63 y.o. male with exercise intolerance, hearing loss, ptosis, and parkinsonism.		(Milone et al., 2011) PubMed
PEO	Found in trans w/ G848S in a 63 y.o. w/ PEO, ptosis, hearing loss, muscle weakness and ragged red fibers	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: c. 3104 +3a→t cDNA Position: 3104 +3a→t (splice variant resulting in a deletion on exon 19)
Disease	Genetics	Frequency	Reference
PEO	Found in compound with the intronic mutation T914P in a 37 y.o. male with PEO. Myopathy, dysphagia, and muscle weakness developed by age 55. Pt.'s older brother was diagnosed with PEO at age 65, and pt.'s adult daughters are not affected. Pt. had COX ne		(Roos et al., 2013) PubMed

Amino Acid Substitution: V1044A cDNA Position: 3131 t→c (exon 20)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans with R722H in a 2.5 y.o. old with epilepsy and encephalopathy	7 of 136 mitochondrial disease Finnish children, and screened against 370 control DNA samples	(Isohanni et al., 2011) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: R1047Q cDNA Position: 3140 g→a (exon 20)
Disease	Genetics	Frequency	Reference
PEO	Sporadic / unknown	Not found in 250 control individuals	(Agostino et al., 2003) PubMed

Amino Acid Substitution: R1047W cDNA Position: 3139 c→t (exon 20)
Disease	Genetics	Frequency	Reference
Alpers	Compound in trans with T851A	Not found in over 200 control alleles	(Wiltshire et al., 2008) PubMed
PEO	Found in trans w/A862T in a 61 y.o. with PEO, ataxia, and mtDNA deletions		(Stewart et al., 2009) PubMed
PEO	Found in trans w/ A862T in a 61 y.o. female with PEO, ptosis, peripheral neuropathy, ataxia, and dysarthria.		(Lax et al., 2012a) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: K1050fsX44 cDNA Position: 3149 del a (exon 20)
Disease	Genetics	Frequency	Reference
Seizures	Found in trans w/ A467T in a 4 y.o. w/ seizures, ataxia, hypotonia, and developmentally delayed.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: G1051R cDNA Position: 3151 g→c (exon 20)
Disease	Genetics	Frequency	Reference
PEO, SANDO	ar Found as compound with H932Y	not seen in 120 control subjects.	(Mancuso et al., 2004a) PubMed
Epilepsy ataxia and developmental delay	Found in trans with R309H in a 32 y.o. male with severe neuropathy, achalasia, epilepsy, and developmentally delayed.		(Pozzo et al., 2017) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: G1051R cDNA Position: 3151 g→a (exon 20)
Disease	Genetics	Frequency	Reference
Hepaticencephalopathy, Alpers-Huttenlocher	Found as compound heterzygous in trans with R869Q in a one year old boy. Death at 1.8 years old.		(Dai et al., 2019) PubMed

Amino Acid Substitution: G1052R cDNA Position: 3154 g→c (exon 20)
Disease	Genetics	Frequency	Reference
MDS	Heterozygous in trans with M459I.		(Puusepp et al., 2018) PubMed

Amino Acid Substitution: G1052S cDNA Position: 3154 g→a (exon 20)
Disease	Genetics	Frequency	Reference
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: G1052D cDNA Position: 3155 g→a (exon 20)
Disease	Genetics	Frequency	Reference
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: N1053fsX6 cDNA Position: ?
Disease	Genetics	Frequency	Reference
Hepatocerebral MDS	Found in trans with W748S. This infant died at 42 months and had epilepsy, autism and multiorgan deterioration triggered by VPA.		Pronicki et al., 2018) PubMed

Amino Acid Substitution: E1054fs cDNA Position: ?
Disease	Genetics	Frequency	Reference
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: M1057T cDNA Position: 3170 t→g (exon 20)
Disease	Genetics	Frequency	Reference
PEO	Found in trans w/F1164I in a71 y.o. with Ophthalmoparesis, ptosis, depression, and muscle weakness.		(Bereau et al., 2016) PubMed

Amino Acid Substitution: P1073L cDNA Position: 3218 c→t (exon 20)
Disease	Genetics	Frequency	Reference
Hepatocerebral - Alpers symptoms	Found in trans w/A467T in 2 pt., in trans w/ W748S in 1 pt., and in trans with G848S in 1 pt. Psychomotor delay, seizures, liver delay, and gastrointestinal dysmotility.		(Kurt et al., 2010) PubMed
Alpers	Found as a compound heterozygote w/ S305R in a 9 mo. pt. w/ Alpers		(Baruffini et al., 2011) PubMed
Failure to thrive	Found in trans w/ G848S in a 2 y.o. w/ hypotonia, and gastro-esophageal reflux.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Myopathy	Found as a heterozygous mutation in a 5 yo female with epilepsy, myopathy, and tubulopathy	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed

Amino Acid Substitution: G1076V cDNA Position: 3227 g→t (exon 20)
Disease	Genetics	Frequency	Reference
PEO	Sporadic / unknown	Not detected in 120 healthy control alleles	(Filosto et al., 2003) PubMed

Amino Acid Substitution: C1077G cDNA Position: 3229 t →g (exon 20)
Disease	Genetics	Frequency	Reference
Seizures	Found in trans w/ A957V in a 2 y.o. w/ seizures, encephalopathy, and hypotonia	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: I1079L cDNA Position: 3235 a→c (exon 20)
Disease	Genetics	Frequency	Reference
adPEO	Heterozygous Hearing loss, and ptosis		(Wong et al., 2008) PubMed

Amino Acid Substitution: S1080T cDNA Position: 3239 g→c (exon 20)
Disease	Genetics	Frequency	Reference
Intracranial calcifications	Found as a heterozygous mutation in a 55 y.o. female with action tremors, peripheral neuropathy, hearing loss, and intracranial calcifications		(Sidirooulos et al., 2013) PubMed

Amino Acid Substitution: S1080I cDNA Position: 3239 g→t (exon 20)
Disease	Genetics	Frequency	Reference
Epilepsy	Found in compound with L79F in an 8 yo female with adrenocortical insufficiency and hypothyroidy	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
Epilepsy	Found in compound with L79F in an 8 yo female with epilepsy, cerebellar ataxia, and ptosis	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed

Amino Acid Substitution: R1081dup cDNA Position: 3240– 3242 ins ccg (R) (exon 20)
Disease	Genetics	Frequency	Reference
Alpers	Found in cis w/ L392V and in trans w/L304R		(Cardenas et al., 2010) PubMed
Seizures	Found in trans w/ L304R in a 1 y.o. w/ seizures and developmentally delayed	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: R1081Q cDNA Position: 3241 c→g (exon 20)
Disease	Genetics	Frequency	Reference
Alpers-like	Found in trans with A862T in a 7 y.o. male with Alpers-like symptoms.		(Ferreira et al., 2011) PubMed
Alpers-like	Found in trans with A862T in a 4 y.o. male with Alpers-like symptoms. Affected sibling		(Ferreira et al., 2011) PubMed
Cerebellar ataxia	Found as a heterozygote in a 29 y.o. female with cerebellar ataxia and diabetes		(Ferreira et al., 2011) PubMed

Amino Acid Substitution: R1081P cDNA Position: 3242 g→c (exon 21)
Disease	Genetics	Frequency	Reference
PEO	Found in trans w/ L304R in a 10 y.o. w/ ataxia, seizures, PEO, and dystonia	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: F1092L cDNA Position: 3276 t→g (exon 21)
Disease	Genetics	Frequency	Reference
	Reference # rs74034411		PubMed

Amino Acid Substitution: S1095R cDNA Position: 3285 c→g (exon 21)
Disease	Genetics	Frequency	Reference
adPEO	Hearing loss, ptosis, Muscle weakness, optic atrophy		(Wong et al., 2008) PubMed
Failure to thrive	ar, found in trans w/ D1184N. Aslo, impaired liver functions, deafness, and demyelating sensomotor neuropathy	<0.5% of Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Hepatic failure	Found in trans w/ A467T in a 6 mo. w/ hypotonia, liver failure, abnormal muscle histology, and developmentally delayed	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Myocerebrohepatopathy	Found w/A467T in a 4 y.o. boy with hypotonia, failure to thrive, and abnormalities in cranial nerve enhancement		(Horst et al., 2014) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in cis w/T251I and P587L with PEO, muscle weakness, ataxia, and polyneuropathy. Similar to SANDO, but no dysarthria.		(Bereau et al., 2016) PubMed
SANO (Sensory Ataxic Neuropathy and Ophthalmoparesis)	Found in trans w/T251I and P587L with ataxia, sensory neruopathy, PEO, deafness, and dysphagia.		(Bereau et al., 2016) PubMed

Amino Acid Substitution: S1095G cDNA Position: 3283, 3284 tc→gg (exon 21)
Disease	Genetics	Frequency	Reference
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: R1096C cDNA Position: 3286 c→t (exon 21)
Disease	Genetics	Frequency	Reference
PEO	Sporadic or ar in PEO	Agostino 2003: Not found in 250 individuals	(Agostino et al., 2003) PubMed
Alpers	Found in trans with P648R in PEO-myopathy. Found as homozygous mutation with Q1236H in Alpers	Not found in 250 control individuals	(Horvath et al., 2006) PubMed
Alpers	Found as compound w/ Q1236H .		(Wong et al., 2008) PubMed
Alpers	Found in trans w/T914P, and homozygous in a 2nd pt.		(Ashley et al., 2008) and a correction in (Ashley et al., 2009) PubMed
Cerebellar ataxia, sensory neuropathy, PEO, and dysphagia	Found with R627Q in a 43 yr. old patient		(Schulte et al., 2009) PubMed
Seizures	Found as a homozygote in an 8 mo. old pt. with encephalopathy and seizures.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found as a homozygote in a 1 y.o. with seizures and liver failure.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Encephalopathy	Found in trans w/ G848S in a 2 y.o. w/ hypotonia, ptosis, hepatic failure, and developmentally delayed.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Seizures	Found as a homozygote in a 2 y.o. w/ seizures, lactic acidosis and developmentally delayed.	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
SANDO	Found in trans w/L591F in a 48 y.o. female with SANDO and dysphagia.		(Kurt et al. 2012) PubMed
PEO	Found in trans w/ W748S in a 49 y.o. male with PEO, ptosis, epilepsy and peripheral neuropathy		(Lax et al., 2012a) PubMed
PEO	Found in trans w/A467T in a 42 y.o. male with PEO, ptosis and sensory neuropathy		(Lax et al., 2012a) PubMed
Alpers	Found in trans with W748S in one baby		(Hayhurst et al., 2019) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: R1096H cDNA Position: 3287 g→a (exon 21)
Disease	Genetics	Frequency	Reference
Alpers	Found as a compound in trans with R627Q	Not found in 250 control individuals	(Horvath et al., 2006) PubMed
Alpers	Found as a homozygous mutation in an 8 month old boy with liver failure and encephalopathy.		(Bijarnia-Mahayet al., 2014) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: N1098K cDNA Position: 3294 t→g (exon 21)
Disease	Genetics	Frequency	Reference
Alpers	Found as a heterozygous mutation in a 6 y.o. female with epilepsy following myoclonic seizures. After 3 years of treatment the patient had major cognitive deterioration and loss of voluntary movement. Family members did not harbor N1098K POLG mutation.		(Iodice et al., 2016) PubMed

Amino Acid Substitution: H1110Y cDNA Position: 3328 c→t (exon 21)
Disease	Genetics	Frequency	Reference
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: S1104C cDNA Position: 3311 c→g (exon 21)
Disease	Genetics	Frequency	Reference
PEO	Sporadic / unknown Found as compound with A467T	Not found in 250 individuals	(Agostino et al., 2003) PubMed
Parkinsonism	Found in trans w/G848S in a 59 y.o. male with mtDNA deletions and cerebellar ataxia		(Lax et al., 2012b) PubMed

Amino Acid Substitution: S1104F cDNA Position: 3311 c→t (exon 21)
Disease	Genetics	Frequency	Reference
Epilepsy	Found with A467T in a 5 y.o. male. Patient also had myopathy and ataxia. In a study using patient fibroblasts, the cells were unable to up regulate mitochondrial biogenesis when exposed to Valproic acid.		(Sitarz et al., 2014) PubMed

Amino Acid Substitution: A1105T cDNA Position: 3313 g→a (exon 21)
Disease	Genetics	Frequency	Reference
PEO	Found as a heterozygous mutation and as a compound heterozygous mutation w/ N468D in 3 patients of the same family all w/PEO	Luoma, 2004: None noted in screening of 1640 healthy Finnish control chromosomes.	(Luoma et al., 2004) PubMed
PEO	Found d as a compound heterozygous mutation w/ N468D in 3 patients w/ mtDNA deletions and mutations. Proposed replication stalling as the principal cause of deletion formation.		(Wanrooij et al., 2004) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: V1106I cDNA Position: 3316 g→a (exon 21)
Disease	Genetics	Frequency	Reference
PEO	ar, found in trans with T251I-P587L	Not found in 500 Italian controls.	(Horvath et al., 2006) PubMed

Amino Acid Substitution: H1110Y cDNA Position: 3328 c→t (exon 21)
Disease	Genetics	Frequency	Reference
infantile hepatocerebral mtDNA depletion	Heterozygous, found in cis Q1236H, & in trans w/ W748S+ E1143G		(Taanman et al., 2008) PubMed

Amino Acid Substitution: L1113P cDNA Position: 3338 t→c (exon 21)
Disease	Genetics	Frequency	Reference
Seizures	Found in trans w/ A467T in a 1 y.o. with encephalopathy, seizures, and hepatic failure	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: R1128H cDNA Position: 3383 g→a (exon 21)
Disease	Genetics	Frequency	Reference
Microcephaly	Heterozygous, found w/ G517V		(Wong et al., 2008) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: H1134R cDNA Position: 3401 a→g (exon 21)
Disease	Genetics	Frequency	Reference
infantile hepatocerebral mtDNA depletion	Heterozygous, found in trans with Y831C		(Taanman et al., 2008) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: E1136K cDNA Position: 3406 g→a (exon 21)
Disease	Genetics	Frequency	Reference
infantile hepatocerebral mtDNA depletion	Heterozygous, found T251I+P587L		(Taanman et al., 2008) PubMed
	Reference # 56047213		PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: R1138C cDNA Position: 3412 c→t (exon 21)
Disease	Genetics	Frequency	Reference
PEO	Found in trans w/ A467T		(Wong et al., 2008) PubMed
SANDO	Found in trans with A67T in a 35 y.o. with PEO, ataxia, sensory neuropathy, muscle weakness, and Chorea.		(Bereau et al., 2016) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: R1142W cDNA Position: 3424 c→t (exon 21)
Disease	Genetics	Frequency	Reference
Neutral polymorphism		0.6% of 450 individuals	(GeneSNPs, 2004) PubMed
	Reference # rs2307442		PubMed

Amino Acid Substitution: E1143G cDNA Position: 3428 a→g (exon 21)
Disease	Genetics	Frequency	Reference
Neutral polymorphism	Neutral polymorphism but may modulate disease mutations	SNP at 3.7% of 450 individuals of European descent. Not found in Asian or African populations	(GeneSNPs, 2004)  PubMed
PEO	Found as a heterozygous mutation	Di Fonzo 2003: Not found in 100 DNA samples from healthy Italians	(Di Fonzo et al., 2003) PubMed
Ataxia	Found as a homozygous and heterozygous mutation, or in compound w/ W748S all within the same family		(Van Goethem et al., 2004) PubMed
Alpers	found in compound with W748S and Y1210fs1216X,		(Ferrari et al., 2005) PubMed
Neutral polymorphism but may modulate disease mutations	Found in cis w/ A889T		(Hisama et al., 2005)  PubMed
Ataxia	Found as a homozygous mutation w/ W748S	Carrier frequency in the general Finnish population of 1:125 from 500 control chromosomes	(Hakonen et al., 2005) PubMed
Alpers	Found in trans w/G848S and in cis w/E1143G in 4 children w/ hepatocerebral disorders and mtDNA depletion	Present in 3-5% of the control population	(Davidzon et al., 2005) PubMed
Alpers	Found in ataxia-neuropathy in cis with W748S and in compound with G848S or A467T.		(Nguyen et al., 2005) PubMed
Ataxia	Found in compound w/ Q497H and W748S	frequency of 0.03	(Winterthun et al., 2005)  PubMed
Ataxia-neuropathy spectrum disorders	Studied the biochemical effects of E1143G in cis with other pathogenic mutations, and how it can modulate the effects of these mutations		(Chan et al., 2006) PubMed
Liver failure, Neuropathy, and PEO	Found in trans w/ A467T/T885S and in cis w/ Q789H in an 2.5 y.o. old male with liver failure. Also found in trans w/A467T in a 15 y.o. male w/ PEO. Found in trans w/ S433C in a 25 y.o. male w/PEO. Found in cis w/ L965X and in trans w/ R627Q/Q1236H in	Not found in 250 control individuals	(Horvath et al., 2006) PubMed
Encephalopathy	Found in compound w/ W748S, A467T R323H, and M1163R in children w/ progressive encephalopathy	Not found in 200 control alleles	(Kollberg et al., 2006) PubMed
Alpers	Found in compound w/ W748S and nt2842_2843insA in children w/ multiple complex deficiencies	Sarzi, et al. 2007 reported 2% (n=50) of patients with multiple respiratory chain deficiency with a 35% decrease of mtDNA were found with the mutation W748S with E1143G.	(Sarzi, et al. 2007) PubMed
Alpers with valproate-induced hepatic failure	Found in cis w/ T885S and A467T, and in trans w/ Q879H		(McFarland et al., 2008) PubMed
Alpers, Ataxia Neuropathy, and arPEO+ Myocerbrohepatopathy (MCHS)	Found in trans w/ G848S, and in cis w/Q497H-W748S.  Also found in trans w/ A467T, and in cis w/ Q497H-W748S. Also in cis w/ E1143 and in trans w/ G737R in MCHS.		(Wong et al., 2008) PubMed
PEO and Ataxia	Found in cis w/ G746S and in trans w/ G848S. In a 2nd pt., found in cis w/W748S and in trans w/ G11D and R852C.		(Stewart et al., 2009) PubMed
mtDNA depletion	In cis w/ W748S and in trans w/ H1110Y+Q1236H		(Taanman et al., 2008) PubMed
Alpers	In cis w/W748S and in trans w/G848S		(Taanman et al., 2008) PubMed
Alpers	Found in cis w/ Q497H and W748S, and in trans w/ G848S.	Found in one child with a normal brain MRI.	(Brunetti-Pierri et al., 2008) PubMed
Lipodystrophy	Increase susceptibility of HIV pt. treated w/D4T to develop lipodystrophy		(Chiappini, et al., 2009) PubMed
PEO, ptosis, polyneuropathy, ataxia, and dysarthria	Found in compound w/ A467T and W748S	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed
Epilepsy and myoclonic	ar, found w/ A467T	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed
	Reference # rs2307441		PubMed
SANDO	Found in trans with A467T and in cis with W748S. Sensory ataxia, dysarthria, and opthalmoplegia.		(Posada et al., 2010) PubMed
Alpers	Found in cis with W748S and in trans with R807C in a 1y.o. with epilepsy and encephalopathy	7 of 136 mitochondrial disease Finnish children, and screened against 370 control DNA samples	(Isohanni et al., 2011) PubMed
Alpers	Found in cis with Q497H and W748S, and in trans with A467T in a 6 y.o. with epilepsy and encephalopathy	7 of 136 mitochondrial disease Finnish children, and screened against 370 control DNA samples	(Isohanni et al., 2011) PubMed
Alpers	Found in cis with W748S and in trans with G8484S in a 11 mo. old with epilepsy and encephalopathy	7 of 136 mitochondrial disease Finnish children, and screened against 370 control DNA samples	(Isohanni et al., 2011) PubMed
Alpers	Found in cis with W748S and in trans with T914P in a 2.5 y.o. with epilepsy and encephalopathy	7 of 136 mitochondrial disease Finnish children, and screened against 370 control DNA samples	(Isohanni et al., 2011) PubMed
VPA-induced liver toxicity	Found in 2 patients ages 26 and 33 with VPA-induced hepatotoxicity as a heterozygous mutation	A frequency 1.9x10e-4 out of 968 alleles of ethnically matched population controls	(Stewart et al., 2010) PubMed
Alpers	Found w/R232H and W748S in a pediatric patient w/mitochondrial encephalomyopathy, seizures, ataxia, and ophthalmological involvement		(Sofou et al., 2012) PubMed
Alpers	Found w/M1163R and W748S in a pediatric patient w/mitochondrial encephalomyopathy, seizures, ataxia, and ophthalmological involvement		(Sofou et al., 2012) PubMed
MIRAS	Mother and son were homozygous for W748S in cis with E1143, and the unaffected father was heterozygous for W748S in cis with E1143G. Both mother and son had decreased mtDNA and spinocerebellar ataxias with presentation in late 30's and early 40's.	Frequencies in Europe for W748S+E1143G or A467T range from 0.6% in Belgium, 0.8% in Finland, and 2% in Finland	(Palin et al., 2012) PubMed
Alpers	Found w/W748S in a 16 mo. boy with epilepsy, mtDNA depletion, and noted defects of the respiratory chain complexes I,II, and IV.		(de Camaret et al., 2014) PubMed
PEO	Found in compound w/A143V and W748S in a 40 y.o. female patient w/ chronic intestinal pseudo-obstruction, PEO, and ataxia.	In 5 out of 80 patients w/ chronic intestinal pseudo-obstruction	(Amiot et al., 2009) PubMed
Inclusion body myositis	Found as a heterozygous mutation in a Swedish patient with Inclusion body myostitis. In addition the patient had COX deficient muscle fibers, ragged red fibers, and mtDNA deletions.	1 in 26 patients with inclusion body myositis. 8 of which had heterozygous POLG mutations.	(Lindgen et al., 2015) PubMed
SCAE	Found in trans wW748S on both allels in a 22 y.o. with cerebellar ataxia, seizures, deafness, migraines, and dystonia		(Bereau et al., 2016) PubMed
SCAE	Found in trans with A467T and in cis W748S in a 36 y.o. with PEO, ataxia, sensory neuropathy, seizures, and migraines.		(Bereau et al., 2016) PubMed
SANDO	Found in cis w/W748S and in trans w/R627Q and Q1236H in a 38 y.o. with sensory neuropathy, ataxia, PEO, and cognitive impairment.		(Bereau et al., 2016) PubMed
SANDO	Found in trans w/R627Q and Q1236H and in cis w/W748S in a 47 y.o. with sensory neuropathy, ataxia, Ophthalmoparesis and muscle weakness.		(Bereau et al., 2016) PubMed
Epilepsy	Heterozygous or homozygous or in trans with Q1236H. No significant risk factors for VHT or pancreatic toxicity.	4.1% in the general European population, 2.8% in the Finnish population and 2.9% in the North American population. However, only a low number or no carriers are found in African, Asian, and Latino populations.	(Hynynen et al., 2018) PubMed
PEO	Found as heterozygous in cis with V1177L with PEO, intolerance to exercise with muscular weakness, and psychiatric problems.		(Blazquez-Bermejo et al., 2019) PubMed

Amino Acid Substitution: D1145GfsX9 cDNA Position: gagg ins at 3433 /3434 (exon 21)
Disease	Genetics	Frequency	Reference
Seizures	Found in trans w/ L304R in a 12 y.o. with hypotonia and developmentally delayed	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: R1146C cDNA Position: 3436 c→t (exon 21)
Disease	Genetics	Frequency	Reference
Neutral polymorphism	SNP	0.6% of 450 individuals	(GeneSNPs, 2004) PubMed
Neutral polymorphism	Found as a heterozygous mutation in a 18 y.o. male with muscle atrophy	24 patients diagnosed with mitochondrial disease and having multiple mtDNA deletions compared to 100 controls in a Spanish population.	(Gonzalez-Vioque et al., 2006) PubMed
	Reference # rs2307440		PubMed

Amino Acid Substitution: Q1154R cDNA Position: 3461 a→g (exon 21)
Disease	Genetics	Frequency	Reference
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: N1157S cDNA Position: 3470 a→g (exon 21)
Disease	Genetics	Frequency	Reference
?	Found in trans w/ T251I and P587L in a 9 y.o. w/ no symptoms noted	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: c.3482 +2t>c cDNA Position: 3482 +2t's splice at intron 21 (exon 21)
Disease	Genetics	Frequency	Reference
Alpers	Exon21/Intron21 splice site mutation at a.a. 1161. Found in trans with A467T in a male child w/ infantile hepatocerbral syndrome		(Ferrari et al., 2005) PubMed

Amino Acid Substitution: c.3626_3629dupGATA cDNA Position:
Disease	Genetics	Frequency	Reference
Alpers	Found in a 1 y.o female with , located 14nt befoer the end of exon 22 resulting in the in a premature stop codon and the skipping of most of exon 22.		(de Camaret et al., 2014) PubMed

Amino Acid Substitution: M1163R cDNA Position: 3488 t→g (exon 22)
Disease	Genetics	Frequency	Reference
Liver failure, encephalopathy, and epilepsy	Found as compound in trans with W748S - E1143G	Not found in 200 control alleles	(Kollberg et al., 2006) PubMed
Alpers	Found w/E1143G and W748S in a pediatric patient w/mitochondrial encephalomyopathy, seizures, ataxia, and ophthalmological involvement		(Sofou et al., 2012) PubMed
MDS	Found in a large cohort study.		(Hikmat et al., 2020) PubMed

Amino Acid Substitution: F1164I cDNA Position: 3490 t→a (exon 22)
Disease	Genetics	Frequency	Reference
PEO	Ar, found in cis with T914P and in trans with Q308H	Not found in 200 Italian controls	(Horvath et al., 2006) PubMed
PEO	Found in trans w/M1057T in a71 y.o. with Ophthalmoparesis, ptosis, depression, and muscle weakness.		(Bereau et al., 2016) PubMed

Amino Acid Substitution: F1164L cDNA Position: 3492 t→ g or a (exon 22)
Disease	Genetics	Frequency	Reference
	Reference # rs62640038		PubMed

Amino Acid Substitution: L1173fsX cDNA Position: 3518 ins gact, fs in exon 22 (exon 22)
Disease	Genetics	Frequency	Reference
Alpers	Compound with A467T	Not found in 300 control chromosomes	(Nguyen et al., 2006) PubMed

Amino Acid Substitution: Q1175R cDNA Position: 3524 a→g (exon 22)
Disease	Genetics	Frequency	Reference
SNP	Reference # rs188348569		PubMed

Amino Acid Substitution: S1176L cDNA Position: 3527 c→t (exon 22)
Disease	Genetics	Frequency	Reference
PEO	Found as a heterozygous mutation	Lamantea, 2002: Not found in a control group of 100 DNA samples from unrelated Italians	(Lamantea et al., 2002) PubMed
PEO	Found in compound w/with T251I/P587L		(Lamantea and Zeviani, 2004) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: V1177L cDNA Position: 3529 g→c (exon 22)
Disease	Genetics	Frequency	Reference
PEO	Found as heterozygous in cis with E1143G with PEO, intolerance to exercise with muscular weakness, and psychiatric problems.		(Blazquez-Bermejo et al., 2019) PubMed

Amino Acid Substitution: D1184L cDNA Position: 3550 g→c (exon 22)
Disease	Genetics	Frequency	Reference
PEO	Found as a compound heterozygote with S998L in a 64 y.o. female with PEO, bilateral ptosis, and encephalopathy.		(Martikainen et al., 2010) PubMed

Amino Acid Substitution: D1184N cDNA Position: 3550 g→a (exon 22)
Disease	Genetics	Frequency	Reference
PEO and tetraparesis	Compound in trans with N468D	24 patients diagnosed with mitochondrial disease and having multiple mtDNA deletions compared to 100 controls in a Spanish population.	(Gonzalez - Vioque et al., 2006) PubMed
Multi-system disorder	Found in compound with R227W in 2 children w/ severe childhood multi-system disorder	de Vries et al. , 2007 identified 1 (4.76%) children out of 21 with a POLG mutation that were known to have a mitochondrial disorder	(de Vries et al., 2007) PubMed
Failure to thrive	ar, found in trans w/ S1095R. Aslo, impaired liver functions, deafness, and demyelating sensomotor neuropathy	<0.5% in Dutch population	(Blok and van den Bosch et al., 2009) PubMed
PEO	Found as a heterozygous mutation in a 70 yo male with PEO, neuronopathy, and parkinsonism	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
PEO	Found as a heterozygous mutation in a 75 yo male with PEO and neuronopathy	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed
PEO	Found in compound w/T251I and P587L in a 33 y.o. female patient w/ chronic intestinal pseudo-obstruction, PEO, and ataxia.	In 5 out of 80 patients w/ chronic intestinal pseudo-obstruction	(Amiot et al., 2009) PubMed
PEO	Found in compound w/P587L and T251I in a 30 y.o. male patient w/ chronic intestinal pseudo-obstruction and PEO.	In 5 out of 80 patients w/ chronic intestinal pseudo-obstruction	(Amiot et al., 2009) PubMed

Amino Acid Substitution: I1185T cDNA Position: 3554 t→c (exon 18)
Disease	Genetics	Frequency	Reference
Myocerebrohepatopathy spectrum disorder	Found in compound w/A957V in an 8 mo. Japanese female. Hypotonia, failure to thrive, hepatomegaly, and developmental regression.	Hetero compound not found in 1000 Genome Project, ESP6500 data base, nor HGVD	(Montassir, et al., 2014) PubMed

Amino Acid Substitution: I1185N cDNA Position: 3554 t→a (exon 18)
Disease	Genetics	Frequency	Reference
Progressive ataxia and Palatal tremor (PAPT)	Found in trans w/W748S in a 52 y.o. male w/ kinetic and static ataxia, dysarthria, palatal trmor, and vertical nystagmus.		(Nicastro et al., 2016) PubMed

Amino Acid Substitution: R1187W cDNA Position: 3559 c→t (exon 22)
Disease	Genetics	Frequency	Reference
	Found in a patient with mitochondrial depletion syndrome and T cell immunodeficiency. Pathogenesis unclear.	Not detected in 100 Turkish control alleles	(Reichenbach et al., 2006) PubMed
Hepatic failure	Found as a heterozygous mutation in a 10 yo male with hepatic failure, myopathy and psychomotor delay	Found in 160 French cohort of potential POLG patients	(Rouzier et al., 2013) PubMed

Amino Acid Substitution: C1188R cDNA Position: 3562 t→c (exon 22)
Disease	Genetics	Frequency	Reference
Seizures	Found in trans w/ A467T in a 3 y.o. w/ seizures, hypotonia, and developmentally delayed	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed

Amino Acid Substitution: K1191N cDNA Position: 3573 g→t (exon 22)
Disease	Genetics	Frequency	Reference
Alpers	Compound in trans with A467T	Not found in 250 control individuals	(Horvath et al., 2006) PubMed
PEO	Found in trans w/ T251I and P587L in a 39 y.o. w/ PEO, neuropathy, ptosis, and muscle weakness	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: K1191R cDNA Position: 3572 a→g (exon 22)
Disease	Genetics	Frequency	Reference
Myocerebrohepatopathy	In trans with T251I-P587L		(Wong et al., 2008) PubMed

Amino Acid Substitution: D1196N cDNA Position: 3586 g→a (exon 22)
Disease	Genetics	Frequency	Reference
Myopathy	In trans w/ G517V		(Wong et al., 2008) PubMed

Amino Acid Substitution: T1199X cDNA Position: 3595 ins. a (exon 22)
Disease	Genetics	Frequency	Reference
Cerebellar ataxia, sensory neuropathy, PEO, and dysphagia	Found with R627Q in a 47 yr. old patient		(Schulte et al., 2009) PubMed

Amino Acid Substitution: c.3600 del T cDNA Position: 3600 deletion of t (exon 22)
Disease	Genetics	Frequency	Reference
Epilepsy	Found with W748S in a 3 y.o. female. Patient also had myopathy. In a study using patient fibroblasts, the cells were unable to up regulate mitochondrial biogenesis when exposed to Valproic acid.		(Sitarz et al., 2014) PubMed

Amino Acid Substitution: G1205A cDNA Position: 3614 g→ c (exon 22)
Disease	Genetics	Frequency	Reference
	Heterozygous w/ Retinitis pigmentosa, hearing loss, failure to thrive		(Wong et al., 2008) PubMed

Amino Acid Substitution: c.3626_3629dupGATA cDNA Position: 3626_3629dupGATA (exon 22 partial skipping)
Disease	Genetics	Frequency	Reference
MNGIE-like syndrome	Found as compound heterozygous in trans with M299L in a 26-year-old male with MNGIE-like syndrome together with leukoencephalopathy and demyelinating neuropathy.		(Yasuda et al., 2019) PubMed

Amino Acid Substitution: Y1210fs1216X cDNA Position: 3630 ins c (exon 22)
Disease	Genetics	Frequency	Reference
Alpers	Found in compound with W748S and E1143G, Mutation causes frame shift to stop at a.a. 1216.		(Ferrari et al., 2005) PubMed
Alpers	Found in 2 infants in compounds w/ W748S		(Spinazzola et al., 2009) PubMed

Amino Acid Substitution: Y1210X cDNA Position: 3630 ? (exon 22)
Disease	Genetics	Frequency	Reference
Hepatocerebral MDS	Found in trans with W748S. This infant died at 35 months and had status epilepticus and liver failure.		Pronicki et al., 2018) PubMed

Amino Acid Substitution: Q1214X cDNA Position: 3640 c→t (exon 22)
Disease	Genetics	Frequency	Reference
PEO	Found in trans w/ S933R in a 60 y.o. w/ PEO, dementia, myopathy, and abnormal muscle histology	Found in a cohort of 2697 patients with suggestive clinical presentations of POLG deficiencies.	(Tang et al., 2011) PubMed
Epilepsy	Found in a cross-sectional study of 22676 genetic variants associated with epilepsy		(SoRelle et al., 2020) PubMed

Amino Acid Substitution: c.3643 + 1G > A cDNA Position: 3643 g→a splice variant (exon 22/23)
Disease	Genetics	Frequency	Reference
MNGIE-like syndrome	Found as heterozygous in trans with S799Y in a 42 year-old man with MNGIE-like syndrome involved leukoencephalopathy.		(Huang et al., 2019) PubMed

Amino Acid Substitution: c.3643+2t>c cDNA Position: 3645 t→c splice variant(exon 22/23)
Disease	Genetics	Frequency	Reference
Alpers	Found in trans w/ A467T		(Roels, et al., 2009) PubMed

Amino Acid Substitution: A1217P cDNA Position: 3649 g→c (exon 23)
Disease	Genetics	Frequency	Reference
Epilepsy	Found as heterozygous in trans with N864S in a 3-year-old girl presented with severe epilepsy in the context of Borrelia infection.		(Gaudó et al., 2020) PubMed

Amino Acid Substitution: S1230F cDNA Position: 3689 c→t (exon 23)
Disease	Genetics	Frequency	Reference
Neutral polymorphism		<1 % in control populations	(Luoma et al., 2007) PubMed
	Found in a Chinese population with Parkinsonism at an allelic frequency of 0.453	344 Chinese parkinson patients and 144 controls	(Gui et al., 2012) PubMed

Amino Acid Substitution: Q1236H cDNA Position: 3708 g→t (exon 23)
Disease	Genetics	Frequency	Reference
Neutral polymorphism		4.0% of 450 individuals	(GeneSNPs, 2004)  PubMed
Neutral polymorphism	Found in 5 PEO patients as a heterozygous mutation	Di Fonzo 2003: Not found in 100 DNA samples from healthy Italians	(Di Fonzo et al., 2003)  PubMed
Neutral polymorphism	Found in cis with R627Q in trans with A467T in a family w/ ataxia - myopathy and ptosis		(Luoma et al., 2005) PubMed
Alpers	Found in trans with A467T, and in cis w/ T849H. Also found as a compound w/ R1096C.		(Wong et al., 2008) PubMed
mtDNA depletion	In cis w/ H1110Y and in trans w/ E1143G+W748S		(Taanman et al., 2008) PubMed
	Reference # rs3087374		PubMed
VPA induced liver toxicity	Found in 5 patients ages 2 to 47 with VPA-induced hepatotoxicity as a heterozygous mutation	A frequency 1.9x10e-4 out of 968 alleles of ethnically matched population controls	(Stewart et al., 2010) PubMed
	Found in a Chinese population with Parkinsonism at an allelic frequency of 0.281	344 Chinese parkinson patients and 144 controls	(Gui et al., 2012) PubMed
Sensory axonal neuronopathy	Found in a 67 y.o. female and her 61 y.o. brother. Found in compound w/Y837C, D122Y, K601E. Both patients have an ataxia, dysarthria, seizures, and sensory neuropathies.	Not found in 200 chromosomes controls	(Zabalza et al., 2014) PubMed
Inclusion body myositis	Found as a heterozygous mutation in 5 unrelated Swedish patients with Inclusion body myostitis. All patients had COX deficient muscle fibers, ragged red fibers, and mtDNA deletions.	5 in 26 patients with inclusion body myositis. 8 of which had heterozygous POLG mutations.	(Lindgen et al., 2015) PubMed
SANDO	Found in cis w/R627Q and in trans w/W748S and E1143G in a 38 y.o. with sensory neuropathy, ataxia, PEO, and cognitive impairment.		(Bereau et al., 2016) PubMed
SANDO	Found in cis w/R627Q and in trans w/W748S and E1143G in a 47 y.o. with sensory neuropathy, ataxia, Ophthalmoparesis and muscle weakness.		(Bereau et al., 2016) PubMed
Progressive multi-systemic disorder	Found in cis w/Y955H in an 8 month old with weight loss, hearing loss, myopathy, liver failure, decreased ATP production, COX negative muscle fibers, and ragged red fibers.		(Siibak et al., 2017) PubMed
PEO	Found in trans w/G517V in a 23 y.o. with PEO and hypostenia.		(Pozzo et al., 2017) PubMed
Epilepsy	Heterozygous or homozygous or in trans with W748S or E1143G. No significant risk factors for VHT or pancreatic toxicity.	8.3% in the European population, 14.8%?15.9% in the Finnish population and about 1% in Africans and Asians.	(Hynynen et al., 2018) PubMed

Amino Acid Substitution: X1240Q+35a.a. cDNA Position: 3718 t→c +35aa (exon 23)
Disease	Genetics	Frequency	Reference
PEO	Found in trans w/A467T in a 50 y.o. male with arPEO and sensory neuropathy		(Lax et al., 2012b) PubMed

Amino Acid Substitution: X1240Y+35a.a. cDNA Position: 3720 g→c +35aa (exon 23)
Disease	Genetics	Frequency	Reference
PEO	Found in trans w/A467T in a 42 y.o. female with PEO, ptosis and sensory neuropathy		(Lax et al., 2012a) PubMed

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