ClinVar Miner

Submissions for variant NM_000891.3(KCNJ2):c.226T>G (p.Cys76Gly)

dbSNP: rs786205812
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170974 SCV000223537 likely pathogenic not provided 2017-01-04 criteria provided, single submitter clinical testing p.Cys76Gly (TGT>GGT): c.226 T>G in exon 2 of the KCNJ2 gene (NM_000891.2). The Cys76Gly variant in the KCNJ2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Cys76Gly results in a non-conservative amino acid substitution of a polar Cysteine with a non-polar Glycine at a position that is highly conserved across species. Consequently, in silico analysis predicts Cys76Gly is damaging to the protein structure/function. Mutations in nearby residues (Asp71Asn, Asp71Tyr, Asp71Val, Thr74Ala, Thr75Ala, Thr75Arg, Thr75Met) have been reported in association with LQTS/ATS, further supporting the functional importance of this region of the protein. In addition, the Cys76Gly variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Cys76Gly is a good candidate for a disease-causing mutation. The variant is found in CPVT panel(s).
Labcorp Genetics (formerly Invitae), Labcorp RCV000471851 SCV000541385 uncertain significance Andersen Tawil syndrome; Short QT syndrome type 3 2016-06-13 criteria provided, single submitter clinical testing In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCNJ2-related disease. ClinVar contains an entry for this variant (Variation ID: 190808). This sequence change replaces cysteine with glycine at codon 76 of the KCNJ2 protein (p.Cys76Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine.

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