ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.3346A>G (p.Met1116Val) (rs201144044)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188618 SCV000242241 uncertain significance not provided 2017-02-24 criteria provided, single submitter clinical testing The M1116V variant in the POLG gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The M1116V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M1116V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret M1116V as a variant of uncertain significance.
Invitae RCV000552872 SCV000630146 uncertain significance Progressive sclerosing poliodystrophy 2017-04-11 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 1116 of the POLG protein (p.Met1116Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs201144044, ExAC 0.001%) but has not been reported in the literature in individuals with a POLG-related disease. ClinVar contains an entry for this variant (Variation ID: 206561). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000188618 SCV001334800 uncertain significance not provided 2020-02-01 criteria provided, single submitter clinical testing

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