ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.926G>A (p.Arg309His) (rs780953863)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000421279 SCV000520840 likely pathogenic not provided 2016-01-20 criteria provided, single submitter clinical testing A published R309H variant that is likely pathogenic has been identified in the POLG gene. The R309H variant hasbeen reported previously in an individual with encephalopathy and liver failure who also had a second POLG variantidentified on the other allele (Horvath et al., 2006; Szczepanowska et al., 2010). Functional studies suggest that theR309H variant results in mtDNA instability (Szczepanowskaet al., 2010). It was not observed in approximately 6,500 individuals of European and African American ancestry inthe NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Thissubstitution occurs at a position that is conserved across species. Additionally, different missense variants at the samecodon (R309C, R309L) as well as multiple missense variants in nearby residues have been reported in the HumanGene Mutation Database in association with POLG-related disorders (Stenson et al., 2014), supporting the functionalimportance of this region of the protein. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. However, the R309H variant is a conservative amino acid substitution, which is not likely toimpact secondary protein structure as these residues share similar properties. Therefore, this variant is likelypathogenic; however, the possibility that it is benign cannot be excluded.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000421279 SCV001149573 likely pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000421279 SCV001190063 uncertain significance not provided no assertion criteria provided provider interpretation

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