Submissions for variant NM_002693.3(POLG):c.2243G>C (p.Trp748Ser)

gnomAD frequency: 0.00076  dbSNP: rs113994097

Total submissions: 44

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000080023	SCV000242192	pathogenic	not provided	2020-01-21	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20691285, 21956653, 21455106, 25713120, 21880868, 22616202, 20438629, 25025039, 22189570, 25497598, 21515089, 23448099, 23808377, 21993618, 23212759, 22166854, 20576279, 20818383, 21236670, 22931735, 25585994, 15477547, 17088268, 24841123, 20153822, 26755490, 27290639, 28130605, 27450679, 26104464, 27822509, 23248042, 26607151, 26942291, 15824347, 18991199, 29482223, 28471437, 18546343, 18321754, 24725338, 19566497, 18294203, 24122062, 30306720, 29655203, 30423451, 31164858, 27422324, 30860128, 30843307, 31980526, 31475037, 32445240, 33469851, 33300680, 32964447)
Eurofins Ntd Llc (ga)	RCV000080023	SCV000331432	pathogenic	not provided	2016-02-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000313739	SCV000394279	pathogenic	POLG-Related Spectrum Disorders	2016-06-14	criteria provided, single submitter	clinical testing	Across a selection of available literature, the c.2243G>C (p.Trp748Ser) variant has been identified in a total of 86 patients with POLG-related spectrum disorders including 52 in a homozygous state, 31 in a compound heterozygous state, and three in a heterozygous state (Van Goethem et al. 2004; Hakonen et al. 2005; Tzoulis et al. 2006; Tang et al. 2012). Several of these studies indicate that this variant appears to be in cis with a second missense variant, c.3428A>G (p.Glu1143Gly), which is a relatively common variant suggested by Hankonen et al. (2005) to be a polymorphism. The p.Trp748Ser variant has also been detected in a heterozygous state in unaffected family members (Van Goethem et al. 2004). This p.Trp748Ser variant was reported in two of 976 control chromosomes and at a frequency of 0.00566 in the European (Finnish) population of the Exome Aggregation Consortium. Tang et al. (2012) suggest that the Trp248 residue is evolutionarily conserved. Functional studies have been conducted to evaluate the role of the p.Trp748Ser variant on DNA polymerase catalytic activity and binding affinity. Expression of DNA polymerase with wild-type or variant p.Trp748Ser cDNA in baculovirus-infected Sf9 cells showed a decrease in catalytic activity compared to wild type (Chan et al. 2006), but this was not observed in another study (Palin et al. 2012). Both studies showed a decrease in binding affinity of DNA polymerase to DNA in the presence of the p.Trp748Ser variant, at 1.6-fold and 8-fold reduction, respectively. Based on the collective evidence, the p.Trp748Ser variant is classified as pathogenic for POLG-related spectrum disorders.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507757	SCV000604905	pathogenic	not specified	2017-03-25	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000080023	SCV000614711	pathogenic	not provided	2024-02-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This is the second most common pathogenic POLG variant, accounting for approximately 8% of disease-causing alleles (PMID: 20301791, 21880868). This variant segregates with disease in multiple families. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000014461	SCV000630126	likely pathogenic	Progressive sclerosing poliodystrophy	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 748 of the POLG protein (p.Trp748Ser). This variant is present in population databases (rs113994097, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive POLG-related disease (PMID: 15477547, 16080118, 16638794, 17894835, 18294203, 18546343, 22166854, 22931735). It is commonly reported in individuals of Finnish ancestry (PMID: 16080118). ClinVar contains an entry for this variant (Variation ID: 13507). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on POLG function (PMID: 17088268, 20153822). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000080023	SCV000802086	pathogenic	not provided	2021-04-30	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000014459	SCV000803580	pathogenic	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	2023-10-31	criteria provided, single submitter	curation	This variant is interpreted as Pathogenic for Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE). The following ACMG Tag(s) were applied: PM2 =>Absent from controls (or at extremely low frequency if recessive) in gnomAD. PM3_very strong => For recessive disorders, detected in trans with a pathogenic variant (PMID: 15477547; 15929042; 15824347; 18828154; 19578034). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:15477547). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-moderate => Well-established functional studies show a deleterious effect (PMID:17088268).
Ambry Genetics	RCV002313710	SCV000848339	pathogenic	Inborn genetic diseases	2023-08-23	criteria provided, single submitter	clinical testing	The c.2243G>C (p.W748S) alteration is located in exon 13 (coding exon 12) of the POLG gene. This alteration results from a G to C substitution at nucleotide position 2243, causing the tryptophan (W) at amino acid position 748 to be replaced by a serine (S). Based on the available evidence, this alteration is classified as pathogenic for autosomal recessive POLG-related mitochondrial disorders; however, its clinical significance for autosomal dominant progressive external ophthalmoplegia is uncertain. Based on data from gnomAD, the C allele has an overall frequency of 0.099% (280/282688) total alleles studied. The highest observed frequency was 0.621% (156/25104) of European (Finnish) alleles. The c.2243G>C (p.W748S) alteration accounts for approximately 8% of disease causing alleles in the Finnish population. This alteration has been identified in the homozygous state and in conjunction with another alteration in POLG in multiple individuals with Alpers-Huttenlocher syndrome (AHS), sensory ataxic neuropathy, dysarthria/dysphagia, and external ophthalmoplegia (SANDO), and other autosomal recessive POLG-related mitochondrial disorders (Bychkov, 2021; Masingue, 2019; Henao, 2016; Hakonen, 2007; Janssen, 2016; Uusimaa, 2008). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000014461	SCV000887113	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.2243G>C (NP_002684.1:p.Trp748Ser) [GRCH38: NC_000015.10:g.89323426C>G] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17088268 ; 21880868 . 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000313739	SCV000967582	pathogenic	POLG-Related Spectrum Disorders	2018-08-23	criteria provided, single submitter	clinical testing	The p.Trp748Ser variant in POLG has been reported in the homozygous or compound heterozygous state in >20 individuals with POLG-related mitochondrial disorders (Tang 2011, Brunetti-Pierri 2008, Tzoulis 2009, Nicastro 2016, Arkadir 2015, Leh mann 2016). This variant has also been reported in ClinVar (Variation ID# 13507) and has been identified in 0.636% (164/25774) of Finnish chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). However, th is frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Trp748Ser variant m ay impact protein function (Chan 2006); however, these types of assays may not a ccurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for POLG-related mitochondrial disorders in an a utosomal recessive manner based upon presence in affected individuals and functi onal evidence. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PP3.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV001198081	SCV001150218	pathogenic	Mitochondrial DNA depletion syndrome 4b	2022-07-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000080023	SCV001250415	pathogenic	not provided	2025-02-01	criteria provided, single submitter	clinical testing	POLG: PM3:Very Strong, PM2, PP3, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198081	SCV001368866	pathogenic	Mitochondrial DNA depletion syndrome 4b	2019-06-10	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP1,PP3,PP4.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000014461	SCV001440549	pathogenic	Progressive sclerosing poliodystrophy	2022-08-31	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_002693.3:c.2901_2907del._x000D_ Criteria applied: PM3_VSTR, PS3, PP4
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000080023	SCV001448144	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000080023	SCV001449647	pathogenic	not provided	2017-02-15	criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV000014459	SCV001519174	pathogenic	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	2021-01-04	criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000080023	SCV002024710	likely pathogenic	not provided	2023-08-09	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000080023	SCV002501869	likely pathogenic	not provided	2022-03-15	criteria provided, single submitter	clinical testing
Mendelics	RCV002247336	SCV002518885	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1	2022-05-04	criteria provided, single submitter	clinical testing
3billion	RCV000014461	SCV002573228	pathogenic	Progressive sclerosing poliodystrophy	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.099%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013507). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 18991199). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 18991199). A different missense change at the same codon (p.Trp748Cys) has been reported to be associated with POLG-related disorder (PMID: 26169155). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center	RCV000014461	SCV002579578	pathogenic	Progressive sclerosing poliodystrophy	2022-02-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000313739	SCV004122808	pathogenic	POLG-Related Spectrum Disorders	2023-10-12	criteria provided, single submitter	clinical testing	Variant summary: POLG c.2243G>C (p.Trp748Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00097 in 251290 control chromosomes. c.2243G>C has been reported in the literature in multiple individuals affected with POLG-Related Spectrum Disorders as both homozygote and compound heterozygote genotypes (e.g. Tzoulis_2006). 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. The most pronounced variant effect results in <10% of normal activity (e.g. Chan_2006). The following publications have been ascertained in the context of this evaluation (PMID: 17088268, 16638794). 29 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=25), likely pathogenic (n=3), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000014461	SCV004205852	pathogenic	Progressive sclerosing poliodystrophy	2024-03-30	criteria provided, single submitter	clinical testing
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV000014461	SCV004543838	pathogenic	Progressive sclerosing poliodystrophy	2023-05-26	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000014459	SCV004812157	pathogenic	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	2020-08-18	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PM3_STR,PS4_MOD,PP3
Neuberg Centre For Genomic Medicine, NCGM	RCV000014459	SCV005061102	pathogenic	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis		criteria provided, single submitter	clinical testing	The missense c.2243G>C (p.Trp748Ser) in the POLG gene has been observed in individual(s) with autosomal recessive POLG-related disease (Chan, Sherine S L et al.,2006). It is commonly reported in individuals of Finnish ancestry. Functional studies have been conducted to evaluate the role of the p.Trp748Ser variant on DNA polymerase catalytic activity and binding affinity. Expression of DNA polymerase with wild-type or variant p.Trp748Ser cDNA in baculovirus-infected Sf9 cells showed a decrease in catalytic activity compared to wild type (Chan et al. 2006), but this was not observed in another study (Palin et al. 2012). This variant is reported with the allele frequency (0.09%) in the gnomAD Exomes. It is submitted to ClinVar as uncertain Significance/ Likely Pathogenic/ Pathogenic (multiple submissions). Multiple lines of computational evidence predicts a damaging effect on protein structure and function for this variant (Polyphen – score1.00; Sift – score 0.01; Mutation Taster – score 1.00). The amino acid Trptophan at position 748 is changed to a Serine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Trp748Ser in POLG is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000508846	SCV005399256	pathogenic	Mitochondrial disease	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with POLG-related mitochondrial disorders. (I) 0108 - This gene is associated with both recessive and dominant disease. Variants are usually inherited in a recessive manner, however progressive external ophthalmoplegia can also be dominant when heterozygous variants are located in the highly conserved active site of motif B of the polymerase domain (PMID: 30451971). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 30423451). (I) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 280 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with autosomal recessive with POLG-related mitochondrial disorder. In addition, it has been reported in affected and unaffected carriers, which could be due to variable expressivity or potentially missed second variant (ClinVar, PMID: 30423451, PMID: 34288125). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005007848	SCV005633402	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	2024-05-21	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003985719	SCV005900692	pathogenic	POLG-related disorder	2023-12-06	criteria provided, single submitter	clinical testing	The c.2243G>C (p.Trp748Ser) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a compound heterozygous or homozygous change in multiple individuals with autosomal recessive POLG-related disorders (PMID: 15477547, 16080118, 16638794, 17894835, 18294203, 18546343, 22166854, 22931735, 26104464). The c.2243G>C (p.Trp748Ser) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.1% (280/282688), and is absent in the homozygous state. The allele frequency in the Finnish population is 0.6% (156/25104) in gnomAD, and the variant is considered to demonstrate a founder effect (PMID: 16080118). Based on the available evidence, the c.2243G>C (p.Trp748Ser) variant is classified as Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005364879	SCV005916397	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	2023-08-24	criteria provided, single submitter	research
OMIM	RCV000014459	SCV000034710	pathogenic	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	2007-12-01	no assertion criteria provided	literature only
OMIM	RCV000014460	SCV000034711	pathogenic	Spinocerebellar ataxia with epilepsy	2007-12-01	no assertion criteria provided	literature only
OMIM	RCV000014461	SCV000034712	pathogenic	Progressive sclerosing poliodystrophy	2007-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000508846	SCV000040909	not provided	Mitochondrial disease		no assertion provided	literature only
Wellcome Centre for Mitochondrial Research, Newcastle University	RCV000508846	SCV000575916	pathogenic	Mitochondrial disease	2017-04-07	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000014459	SCV000809069	pathogenic	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	2018-03-19	flagged submission	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000080023	SCV001742213	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000080023	SCV001931520	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000080023	SCV001953092	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000080023	SCV001967093	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000080023	SCV002075066	not provided	not provided		no assertion provided	phenotyping only	Variant identified in multiple registry participants. Variant interpreted as Pathogenic and reported on 11-07-2019 by Lab or GTR ID 26957. Variant interpreted as Uncertain significance and reported on 01-03-2018 by Lab or GTR ID 500031. 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.
PreventionGenetics, part of Exact Sciences	RCV003985719	SCV004772400	pathogenic	POLG-related disorder	2024-05-02	no assertion criteria provided	clinical testing	The POLG c.2243G>C variant is predicted to result in the amino acid substitution p.Trp748Ser. This variant has been documented as pathogenic for autosomal recessive POLG-related disorders (Tang et al. 2011. PubMed ID: 21880868). It is a common founder variant for autosomal recessive progressive ataxia in the Finnish population (Hakonen et al. 2005. PubMed ID: 16080118). This variant is reported in 0.62% of alleles in individuals of European (Finnish) descent in gnomAD. In summary, this variant is interpreted as pathogenic.