Submissions for variant NM_002693.3(POLG):c.2542G>A (p.Gly848Ser)

gnomAD frequency: 0.00028  dbSNP: rs113994098

Total submissions: 38

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Courtagen Diagnostics Laboratory, Courtagen Life Sciences	RCV000014451	SCV000236513	pathogenic	Progressive sclerosing poliodystrophy	2014-06-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000188580	SCV000242202	pathogenic	not provided	2020-02-27	criteria provided, single submitter	clinical testing	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)
Eurofins Ntd Llc (ga)	RCV000188580	SCV000331837	pathogenic	not provided	2016-08-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000363602	SCV000394274	pathogenic	POLG-Related Spectrum Disorders	2017-08-28	criteria provided, single submitter	clinical testing	The POLG c.2542G>A (p.Gly848Ser) missense variant is well-documented as one of the three most common pathogenic disease-causing variants found in patients with POLG-related disorders (Cohen et al. 2014). Haplotype analysis suggests it is most likely derived from a single ancient ancestor of European origin (Hakonen et al. 2007). The p.Gly848Ser variant has been reported in association with varied autosomal recessive phenotypes, but not in association with autosomal dominant POLG-related disorders. Across a selection of the available literature, the p.Gly848Ser variant is reported in a homozygous state in one individual with seizures who died suddenly at age five, and in a compound heterozygous state in three individuals with autosomal recessive progressive external ophthalmoplegia, two individuals with sensory ataxia neuropathy dysarthria and ophthalmoplegia, two individuals with Alpers syndrome and one individual with intractable epilepsy (Lamantea et al. 2002; Weiss et al. 2010; Milone et al. 2011; Gáti et al. 2011; Tang et al. 2011; Lax et al. 2012; Scalais et al. 2012; Uusimaa et al. 2013; Simon et al. 2014). It was also identified in one individual with progressive external ophthalmoplegia in a double heterozygous state along with a missense variant in the C10orf2 gene (Van Goethem et al. 2003). The p.Gly848Ser variant has also been identified in three unaffected heterozygous individuals (Lamantea et al. 2002). Segregation analysis in multiple families showed the p.Gly848Ser variant segregated with POLG-related disorders. The variant is absent from 200 control individuals and from 180 control chromosomes (Lamantea et al. 2002; Van Goethem et al. 2003; Tang et al. 2011) and is reported at a frequency of 0.00034 in the European (non-Finnish) population of the Genome Aggregation Database. 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. Based on the collective evidence, the p.Gly848Ser variant is classified as pathogenic for POLG-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000188580	SCV000511422	pathogenic	not provided	2017-01-05	criteria provided, single submitter	clinical testing
Invitae	RCV000014451	SCV000543865	pathogenic	Progressive sclerosing poliodystrophy	2024-01-29	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000515163	SCV000611298	pathogenic	Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b	2022-03-12	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000188580	SCV000614716	pathogenic	not provided	2021-04-30	criteria provided, single submitter	clinical testing	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.
SIB Swiss Institute of Bioinformatics	RCV000014451	SCV000803530	pathogenic	Progressive sclerosing poliodystrophy	2018-05-31	criteria provided, single submitter	curation	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).
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000678386	SCV000804455	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1	2017-09-07	criteria provided, single submitter	provider interpretation	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).
Ambry Genetics	RCV002313707	SCV000848835	pathogenic	Inborn genetic diseases	2017-01-27	criteria provided, single submitter	clinical testing	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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000014451	SCV000887116	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000188580	SCV000892141	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	POLG: PM3:Very Strong, PM2, PP3, PS3:Supporting
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001027839	SCV001190459	pathogenic	Progressive sclerosing poliodystrophy; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b	2021-03-30	criteria provided, single submitter	clinical testing	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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000188580	SCV001447477	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000014451	SCV001554491	pathogenic	Progressive sclerosing poliodystrophy		criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001027839	SCV001984826	pathogenic	Progressive sclerosing poliodystrophy; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b	2020-07-21	criteria provided, single submitter	clinical testing	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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000188580	SCV002010403	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000188580	SCV002019466	pathogenic	not provided	2022-02-15	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847601	SCV002105571	pathogenic	Hereditary spastic paraplegia	2018-11-01	criteria provided, single submitter	clinical testing
DASA	RCV000363602	SCV002107104	pathogenic	POLG-Related Spectrum Disorders	2022-03-05	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics, University Hospital Muenster	RCV002054437	SCV002496144	pathogenic	Progressive sclerosing poliodystrophy; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Mitochondrial DNA depletion syndrome 4b	2022-01-20	criteria provided, single submitter	clinical testing	ACMG categories: PS3,PM1,PM2,PP3,PP5,BP1
Genetics and Molecular Pathology, SA Pathology	RCV000678386	SCV002761805	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1	2021-04-17	criteria provided, single submitter	clinical testing	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230362	SCV003929297	pathogenic	Mitochondrial DNA depletion syndrome	2023-04-11	criteria provided, single submitter	clinical testing	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.
Daryl Scott Lab, Baylor College of Medicine	RCV003231103	SCV004102724	pathogenic	POLG-related disorder	2023-11-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003231103	SCV004120250	pathogenic	POLG-related disorder	2022-12-21	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000014451	SCV004205836	pathogenic	Progressive sclerosing poliodystrophy	2023-10-30	criteria provided, single submitter	clinical testing
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV000014451	SCV004543837	pathogenic	Progressive sclerosing poliodystrophy	2023-05-26	criteria provided, single submitter	clinical testing
OMIM	RCV000014449	SCV000034699	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2009-03-24	no assertion criteria provided	literature only
OMIM	RCV000014450	SCV000034700	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, digenic	2009-03-24	no assertion criteria provided	literature only
OMIM	RCV000014451	SCV000034701	pathogenic	Progressive sclerosing poliodystrophy	2009-03-24	no assertion criteria provided	literature only
OMIM	RCV000014452	SCV000034702	pathogenic	Mitochondrial DNA depletion syndrome 4b	2009-03-24	no assertion criteria provided	literature only
GeneReviews	RCV002272018	SCV000040910	not provided	Mitochondrial disease		no assertion provided	literature only
GenomeConnect, ClinGen	RCV003231103	SCV000607021	not provided	POLG-related disorder		no assertion provided	phenotyping only	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000188580	SCV001740770	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000188580	SCV001807715	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000188580	SCV001955119	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000188580	SCV001965694	pathogenic	not provided		no assertion criteria provided	clinical testing