ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.131A>G (p.Gln44Arg) (rs757120802)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724683 SCV000227269 uncertain significance not provided 2017-05-02 criteria provided, single submitter clinical testing
GeneDx RCV000175731 SCV000581756 uncertain significance not specified 2017-10-26 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the POLG gene. The Q44R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 5,500 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 Q44R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000551143 SCV000630091 uncertain significance Progressive sclerosing poliodystrophy 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 44 of the POLG protein (p.Gln44Arg). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs757120802, ExAC 0.03%). This variant has not been reported in the literature in individuals with a POLG-related disease. ClinVar contains an entry for this variant (Variation ID: 195177). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on POLG function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000551143 SCV000887093 likely benign Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.131A>G (NP_002684.1:p.Gln44Arg) [GRCH38: NC_000015.10:g.89333624T>C] variant in POLG gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BP3:This variant results in inframe indel in repeats without known function. 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 Likely Benign.

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