ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.2791C>A (p.Leu931Ile)

dbSNP: rs1567186644
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758458 SCV000887168 uncertain significance Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2791C>A (NP_002684.1:p.Leu931Ile) [GRCH38: NC_000015.10:g.89320956G>T] variant in POLG gene is interpretated to be a Uncertain Significance 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. BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000758458 SCV001570072 uncertain significance Progressive sclerosing poliodystrophy 2023-01-14 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 931 of the POLG protein (p.Leu931Ile). This variant is not present in population databases (gnomAD no frequency). 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: 619424). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLG protein function. 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.

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