ClinVar Miner

Submissions for variant NM_000891.3(KCNJ2):c.653G>T (p.Arg218Leu)

dbSNP: rs199473384
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170983 SCV000223546 likely pathogenic not provided 2021-04-29 criteria provided, single submitter clinical testing Reported in a patient with premature ventricular contractions (PVCs), frequent ventricular ectopy, bidirectional VT and ventricular arrhythmia suppression with sinus tachycardia who was previously tested at GeneDx (Van Ert et al., 2017); Reported in ClinVar (ClinVar Variant ID# 190813; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31020160, 28491792, 32959505)
Labcorp Genetics (formerly Invitae), Labcorp RCV000470921 SCV000541388 uncertain significance Andersen Tawil syndrome; Short QT syndrome type 3 2016-07-16 criteria provided, single submitter clinical testing In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. A different missense substitution at this codon (p.Arg218Trp) has been determined to be pathogenic (PMID: 11371347, 12909315, 25415519, 14522976, 20647529). This suggests that the arginine residue is critical for KCNJ2 protein function and that other missense substitutions at this position may also be pathogenic. 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. 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. This sequence change replaces arginine with leucine at codon 218 of the KCNJ2 protein (p.Arg218Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine.

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