ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.3505G>A (p.Gly1169Ser)

gnomAD frequency: 0.00001  dbSNP: rs753864625
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188625 SCV000242248 uncertain significance not provided 2019-02-15 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics RCV000765234 SCV000896470 uncertain significance 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 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000188625 SCV001149554 uncertain significance not provided 2016-11-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001321540 SCV001512375 uncertain significance Progressive sclerosing poliodystrophy 2024-12-02 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 1169 of the POLG protein (p.Gly1169Ser). This variant is present in population databases (rs753864625, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 206568). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences RCV003985758 SCV004107438 uncertain significance POLG-related disorder 2022-08-30 criteria provided, single submitter clinical testing The POLG c.3505G>A variant is predicted to result in the amino acid substitution p.Gly1169Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-89860745-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Genomics England Pilot Project, Genomics England RCV001321540 SCV001760352 likely pathogenic Progressive sclerosing poliodystrophy no assertion criteria provided clinical testing

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