ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.3586G>A (p.Asp1196Asn) (rs765344513)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188628 SCV000242251 uncertain significance not provided 2017-03-22 criteria provided, single submitter clinical testing The D1196N variant has been identified previously in trans with a second POLG variant in a patient with developmental delay, short stature, and myopathy, and the authors considered D1196N a novel variant of unknown significance (Wong et al., 2008). The D1196N variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D1196N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (K1191R/N) have been reported in the Human Gene Mutation Database in association with POLG-related disorders (Stenson et al., 2014). This substitution occurs at a position that is conserved in mammals; however, Asparagine has been seen at this position in evolution. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758333 SCV000886998 likely benign Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.3586G>A (NP_002684.1:p.Asp1196Asn) [GRCH38: NC_000015.10:g.89317433C>T] 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. BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. BP6:Reputable source(s) without shared data suggest the variant is benign. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign.

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