rs113994098

chr15-89321792-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

The NM_002693.3(POLG):c.2542G>A(p.Gly848Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000309 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G848G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:36 O:2
• Conservation: PhyloP100: 7.50

Genes affected

POLG (HGNC:9179): (DNA polymerase gamma, catalytic subunit) Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

POLGARF (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_002693.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 15-89321792-C-T is Pathogenic according to our data. Variant chr15-89321792-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89321792-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.2542G>A	p.Gly848Ser	missense_variant	16/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.*1814G>A		3_prime_UTR_variant	16/23
POLG	NM_001126131.2	c.2542G>A	p.Gly848Ser	missense_variant	16/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.2542G>A	p.Gly848Ser	missense_variant	16/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000147 AC: 37 AN: 251408 Hom.: 0 AF XY: 0.000132 AC XY: 18 AN XY: 135894

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000312 AC: 456 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.000301 AC XY: 219 AN XY: 727232

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000390

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74456

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000357 Hom.: 0

Bravo AF: 0.000181

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000157 AC: 19

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:36 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 02, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 05, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	POLG: PM3:Very Strong, PM2, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 30, 2021	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments demonstrate a loss of >99% of polymerase activity and 5-fold reduction in DNA binding affinity (PMID: 19478085, 21228000). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2020	Accounts for approximately 10% of disease-causing alleles and has been identified in patients with autosomal recessive progressive external ophthalmoplegia (arPEO), Alpers syndrome, Leigh syndrome, SANDO, and other autosomal recessive POLG-related disorders causing epilepsy, ataxia, neuropathy, hepatopathy, and/or myopathy (Tang et al., 2011; Human DNA Polymerase Gamma Mutation Database); Published functional studies demonstrate a damaging effect, resulting in significantly impaired polymerase activity and DNA binding ability (Kasiviswanathan et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27538665, 28130605, 31302675, 22616202, 21670405, 22189570, 22342071, 23448099, 12872260, 18500570, 24272679, 20513108, 20818383, 22006280, 25585994, 26692522, 27538604, 12210792, 17980715, 19478085, 27065468, 28139822, 28154168, 21880868, 18991199, 19766516, 28471437, 29655203, 30167885, 30423451, 30552426, 31996268, 33300680) -

Progressive sclerosing poliodystrophy Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	Jun 12, 2014	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Pathogenic, for Mitochondrial DNA depletion syndrome 4A (Alpers type), in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Common mutation frequently observed in multiple unrelated patients. (PMID:17426723,21880868). PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:19478085). PS3 => Well-established functional studies show a deleterious effect (PMID:19478085). -
Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Oct 01, 2018	The NM_002693.2:c.2542G>A (NP_002684.1:p.Gly848Ser) [GRCH38: NC_000015.10:g.89321792C>T] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:12210792 ; 16177225 . This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	May 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 24, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 848 of the POLG protein (p.Gly848Ser). This variant is present in population databases (rs113994098, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive POLG-related conditions (PMID: 12872260, 17426723, 18500570, 21670405, 21880868, 22006280, 22189570, 22342071, 22616202). ClinVar contains an entry for this variant (Variation ID: 13502). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects POLG function (PMID: 17980715, 19478085). For these reasons, this variant has been classified as Pathogenic. -

POLG-related disorder Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Nov 10, 2023	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant reported in multiple GenomeConnect participants by GeneDx. Variant interpreted as Pathogenic and reported, most recently, on 2016-10-31. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 21, 2022	The POLG c.2542G>A variant is predicted to result in the amino acid substitution p.Gly848Ser. This variant has been reported to be causative for a variety of autosomal recessive POLG-associated disorders, such as sensory ataxia neuropathy with dysarthria/dysphagia and ophthalmoplegia (SANDO), Alpers’ Syndrome, Leigh-like syndrome, intractable epilepsy, and progressive external ophthalmoplegia (PEO) (Gáti et al. 2011. PubMed ID: 22616202; Simon et al. 2014. PubMed ID : 24272679; Uusimaa et al. 2013. PubMed ID : 23448099; Lamantea et al. 2002. PubMed ID: 12210792). The p.Gly848Ser variant protein retained less than 1% of catalytic activity compared to the wild type enzyme (Kasiviswanathan et al. 2009. PubMed ID: 19478085). This variant is reported in 0.0085% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-89865023-C-T). We classify this variant as pathogenic. -

POLG-Related Spectrum Disorders Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID:19478085; 17980715) - PS3_moderate.The c.2542G>A;p.(Gly848Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13502; PMID: 17426723; PMID: 21880868; PMID: 18500570; PMID: 12872260; PMID: 22616202; PMID: 22006280; PMID: 22342071; PMID: 21670405; PMID: 22189570) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (DNA_pol_A) - PM1. The variant is present at low allele frequencies population databases (rs113994098 – gnomAD 0.001697%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Gly848Ser) was detected in trans with a pathogenic variant (PMID:19478085) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 28, 2017	- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing;provider interpretation	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	Sep 07, 2017	This 7 year old female with autism spectrum disorder was found to carry a paternally inherited missense variant in the POLG gene. Neither she nor her father have any of the features of autosomal dominant POLG-Related Disorder, but it is possible that features have not yet emerged. Metabolic testing has thus far been normal for the patient. The p.G848S variant is a commonly reported pathogenic variant in the POLG gene, representing approximately 10% of disease-causing variants in this gene (Tang et al., 2011). The p.G848S variant was initially identified in a patient with autosomal recessive progressive external ophthalmoplegia (arPEO) and has subsequently been identified in individuals with Alpers syndrome, Leigh syndrome, SANDO, and other POLG-related disorders causing epilepsy, ataxia, neuropathy, hepatopathy, and/or myopathy (Lamantea et al., 2002). This variant alters a highly conserved position in the polymerase domain of POLG, and functional studies indicate that it significantly impairs the enzyme's polymerase activity and DNA binding ability (Kasiviswanathan et al., 2009). -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 17, 2021	The POLG c.2542G>A variant is classified as Pathogenic (PS3, PS4, PP1, PP3) The POLG c.2542G>A variant is a single nucleotide change in exon 16 of the POLG gene, which is predicted to change the amino acid glycine at position 848 in the protein to serine. The variant has been reported in probands with a clinical presentation of progressive external ophthalmoplegia (PS4). Multiple cases reported in literature: 23 entries in ClinVAR ( all P/LP) This variant co-segregates with disease (PP1). PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. Well-established functional studies show a deleterious effect of this variant (PS3). Lamantea et al. (2002) note that the Gly848 residue is highly conserved, and functional studies by Kasiviswanathan et al. (2009) indicate that the p.Gly848Ser variant significantly impairs POLG activity and DNA binding affinity. Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs113994098) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 13502). -

Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	POLG NM_002693.2 exon 16 p.Gly848Ser (c.2542G>A): This variant has been reported in the literature in the compound heterozygous or homozygous state in several individuals with autosomal recessive progressive external opthalmoplegia as well as a wide variety of additional POLG-related phenotypes (Lamantea 2002 PMID:12210792, Weiss 2010 PMID:20513108, Milone 2011 PMID:21670405, Tang 2011 PMID:21880868, Scalais 2012 PMID:22342071, Uusimaa 2013 PMID:23448099, Simon 2014 PMID:2014 PMID:24272679). Literature suggests that this variant is one of the most common pathgenic variants in the POLG gene (Hakonen, 2007 PMID:17426723, Tang 2011 PMID:21880868). This variant is present in 0.03% (40/129136) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-89865023-C-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:13502). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies indicate that this variant leads to decreased enzyme activity and reduced DNA binding affinity (Kasivishwanathan 2009 PMID:19478085). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jul 21, 2020	This variant has been previously reported as a compound heterozygous change in multiple patients with autosomal recessive POLG-related disorders including Alpers-Huttenlocher syndrome (AHS), sensory ataxic neuropathy, optic Atrophy, intractable epilepsy and early onset epileptic encephalopathy (PMID: 12210792, 22189570, 23448099, 30552426, 30423451, 29655203). Functional characterization indicates that the p.Gly848Ser variant, which is located in the thumb domain of the protein and affects a conserved glycine residue upstream of motif polA, results in <1% polymerase activity, and in a defect in DNA binding function (PMID: 19478085). In addition, studies in model organisms indicated that the yeast-equivalent of the p.Gly848Ser variant results in high mtDNA instability (PMID: 17980715). The p.Gly848Ser variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.017% (48/282794) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.2542G>A (p.Gly848Ser) variant on protein function. Based on the available evidence, the c.2542G>A (p.Gly848Ser) variant is classified as Pathogenic. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 24, 2009

- -

Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;C4551995:Mitochondrial DNA depletion syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 12, 2022

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2017

The p.G848S pathogenic mutation (also known as c.2542G>A), located in coding exon 15 of the POLG gene, results from a G to A substitution at nucleotide position 2542. The glycine at codon 848 is replaced by serine, an amino acid with similar properties. This mutation was first described in an individual with progressive external ophthalmoplegia (PEO), cytochrome c oxidase-neg ragged red fibers, and multiple mtDNA deletions in skeletal muscle who was compound heterozygous for another pathogenic POLG alteration (Lamantea E et al. Ann. Neurol., 2002 Aug;52:211-9). This mutation is located in the catalytic polymerase domain and is one of the most common POLG mutations, accounting for approximately 10% of mutant alleles in one large cohort of over 2000 patients with phenotypes suspicious for POLG deficiencies, including autosomal recessive PEO (arPEO), Alpers syndrome, and seizures (Tang S et al. J Med Genet. 2011 Oct;48(10):669-81). Based on the available evidence, p.G848S is classified as a pathogenic mutation. -

Hereditary spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2018

- -

Mitochondrial DNA depletion syndrome 4b Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 24, 2009

- -

Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Jan 20, 2022

ACMG categories: PS3,PM1,PM2,PP3,PP5,BP1 -

Mitochondrial DNA depletion syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 11, 2023

Variant summary: POLG c.2542G>A (p.Gly848Ser) results in a non-conservative amino acid change located in the DNA polymerase gamma, palm domain (IPR047580) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251408 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome (0.00015 vs 0.0035), allowing no conclusion about variant significance. c.2542G>A has been reported in the literature in compound heterozygous and homozygous individuals affected with Mitochondrial DNA Depletion Syndrome - POLG Related (e.g., Tang_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <1% of normal polymerase activity (e.g., Kasiviswanathan_2009). Multiple ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, digenic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 24, 2009

- -

Mitochondrial disease Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.97
MVP		0.98
MPC		0.66
ClinPred		0.74	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.91
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs113994098; hg19: chr15-89865023; COSMIC: COSV99174674; COSMIC: COSV99174674;