ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2642C>T (p.Pro881Leu) (rs375935084)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000734714 SCV000242301 uncertain significance not provided 2018-09-17 criteria provided, single submitter clinical testing The P881L variant in the POLG gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P881L variant is observed in 10/276906 (0.004%) alleles in large population cohorts (Lek et al., 2016). The P881L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P881L as a variant of uncertain significance.
Invitae RCV000690021 SCV000817697 uncertain significance Progressive sclerosing poliodystrophy 2018-06-04 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 881 of the POLG protein (p.Pro881Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs375935084, ExAC 0.01%). This variant has not been reported in the literature in individuals with POLG-related disease. ClinVar contains an entry for this variant (Variation ID: 206611). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000734714 SCV000862878 uncertain significance not provided 2018-08-10 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000690021 SCV000886967 likely pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2642C>T (NP_002684.1:p.Pro881Leu) [GRCH38: NC_000015.10:g.89321217G>A] 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. 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. Based on the evidence criteria codes applied, the variant is suggested to be Likely Pathogenic.
Athena Diagnostics Inc RCV000734714 SCV001145156 uncertain significance not provided 2019-05-10 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001117864 SCV001276097 uncertain significance POLG-Related Spectrum Disorders 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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