ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2620T>A (p.Leu874Met) (rs758402960)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000188585 SCV000257927 uncertain significance not specified 2015-06-17 criteria provided, single submitter clinical testing
GeneDx RCV000766616 SCV000242207 uncertain significance not provided 2015-12-24 criteria provided, single submitter clinical testing p.Leu874Met (TTG>ATG): c.2620 T>A in exon 17 in the POLG gene (NM_002693.2). The L874M variant in the POLG gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The L874M variant was not observed in approximately 6,500 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 L874M 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 in most species, however Methionine is tolerated at this position in another mammalian species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense mutations in nearby residues (R869Q, Q879H) have been reported in association with POLG-related disorders, supporting the functional importance of this region of the protein. Therefore, we interpret L874M as a variant of unknown significance. The variant is found in POLG panel(s).
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758311 SCV000886969 likely pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2620T>A (NP_002684.1:p.Leu874Met) [GRCH38: NC_000015.10:g.89321239A>T] 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. 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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