ClinVar Miner

Submissions for variant NM_001126131.2(POLG):c.2243G>C (p.Trp748Ser) (rs113994097)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000080023 SCV000242192 pathogenic not provided 2019-01-03 criteria provided, single submitter clinical testing The W748S variant in the POLG gene accounts for approximately 8% of disease causing alleles and has been identified in patients with Alpers 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). The W748S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, W748S is considered a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000080023 SCV000331432 pathogenic not provided 2016-02-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Inc RCV000080023 SCV000614711 pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing This is one of the most common POLG pathogenic mutations. The best available variant frequency is uninformative because it is below the disease allele frequency. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Very strong co-segregation with disease. However, available data are from a single family and lack unaffected family members.
Invitae RCV000014461 SCV000630126 likely pathogenic Progressive sclerosing poliodystrophy 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with serine at codon 748 of the POLG protein (p.Trp748Ser). The tryptophan residue is moderately conserved and there is a large physicochemical difference between tryptophan and serine. This variant is present in population databases (rs113994097, ExAC 0.6%). This variant has been reported to segregate with autosomal recessive POLG-related disease in multiple families (PMID: 15477547, 17894835, 18294203, 22166854, 18546343) and is present in homozygosity or in combination with a pathogenic POLG variant in many affected individuals (PMID: 22931735, 16638794). It is commonly referred to as a founder variant in the Finnish population (PMID: 16080118). ClinVar contains entries for this variant (Variation ID: 13507, 157526). Experimental studies do not agree on whether this variant affects protein 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.
SIB Swiss Institute of Bioinformatics RCV000014459 SCV000803580 uncertain significance Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE), 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. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:15477547). PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:26077851) (PMID:15477547). BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:20153822). PS3 => Well-established functional studies show a deleterious effect (PMID:17088268).
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000014459 SCV000809069 pathogenic Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome 2018-03-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000717487 SCV000848339 pathogenic Seizures 2018-04-04 criteria provided, single submitter clinical testing Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
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, Partners HealthCare 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,Klinikum rechts der Isar RCV000014459 SCV001150218 pathogenic Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome 2018-02-27 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000080023 SCV001250415 pathogenic not provided 2020-05-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198081 SCV001368866 pathogenic Neuromuscular disorder 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,PM3,PP3. This variant was detected in heterozygous state.
OMIM RCV000014459 SCV000034710 pathogenic Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome 2007-12-01 no assertion criteria provided literature only
OMIM RCV000014460 SCV000034711 pathogenic Myoclonic epilepsy myopathy sensory ataxia 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 RCV000014459 SCV000040909 pathologic Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome 2012-10-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Wellcome Centre for Mitochondrial Research,Newcastle University RCV000508846 SCV000575916 pathogenic Mitochondrial diseases 2017-04-07 no assertion criteria provided clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000080023 SCV000802086 uncertain significance not provided 2016-03-08 no assertion criteria provided clinical testing

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