ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.3542G>A (p.Ser1181Asn) (rs149921636)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000416245 SCV000493306 uncertain significance not provided 2016-10-01 criteria provided, single submitter clinical testing
Invitae RCV000633559 SCV000754805 uncertain significance Progressive sclerosing poliodystrophy 2017-08-16 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 1181 of the POLG protein (p.Ser1181Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs149921636, 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: 374526). 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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000633559 SCV000886994 uncertain significance Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.3542G>A (NP_002684.1:p.Ser1181Asn) [GRCH38: NC_000015.10:g.89317477C>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. 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 Uncertain Significance.

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