ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2799T>G (p.Ser933Arg) (rs765916932)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497987 SCV000589538 likely pathogenic not provided 2016-04-29 criteria provided, single submitter clinical testing The S933R variant in the POLG gene has been reported previously with POLG-related disorders, in two unrelated affected individuals who were compound heterozygous for the S933R variant and another pathogenic variant (Tang et al., 2011). The S933R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S933R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The S933R variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758459 SCV000887169 likely pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2799T>G (NP_002684.1:p.Ser933Arg) [GRCH38: NC_000015.10:g.89320948A>C] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PM1:This variant is in mutational hot spot or a well-studied functional domain without benign variation. 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. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. 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 Likely Pathogenic.

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