ClinVar Miner

Submissions for variant NM_000891.3(KCNJ2):c.653G>A (p.Arg218Gln)

dbSNP: rs199473384
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000791452 SCV000260176 pathogenic Andersen Tawil syndrome; Short QT syndrome type 3 2023-09-03 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 218 of the KCNJ2 protein (p.Arg218Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Andersen-Tawil syndrome (PMID: 11371347, 12163457, 17211524, 17221872, 22589293, 23644778, 23867365). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67585). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNJ2 protein function. Experimental studies have shown that this missense change affects KCNJ2 function (PMID: 11371347, 12086641, 14522976, 16834334, 22002906). This variant disrupts the p.Arg281 amino acid residue in KCNJ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11371347). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000255682 SCV000321798 pathogenic not provided 2023-07-28 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate this variant exerts a dominant-negative effect on channel function (Bendahhou et al., 2003; Tristani-Firouzi et al., 2002); 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: 17211524, 32843460, 12909315, 22002906, 12163457, 17221872, 23867365, 11371347, 26109178, 16769944, 16834334, 16419128, 30298493, 23644778, 22581653, 12086641, 31509255, 31737537, 32810216, 32383558, 33094497, 33345742, 35460302, 35456365, 14522976, 22589293, 34919635)
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues RCV000157273 SCV000611764 pathogenic Andersen Tawil syndrome 2017-06-22 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000157273 SCV000987445 pathogenic Andersen Tawil syndrome criteria provided, single submitter clinical testing
Ambry Genetics RCV002362693 SCV002658971 pathogenic Cardiovascular phenotype 2019-12-23 criteria provided, single submitter clinical testing The p.R218Q pathogenic mutation (also known as c.653G>A), located in coding exon 1 of the KCNJ2 gene, results from a G to A substitution at nucleotide position 653. The arginine at codon 218 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with Andersen-Tawil syndrome (ATS), and has been reported to segregate with ATS in families (Plaster NM et al. Cell, 2001 May;105:511-9; Haruna Y et al. Hum. Mutat., 2007 Feb;28:208; Jagodziska M et al. Ann Noninvasive Electrocardiol, 2016 Mar;21:189-95; Choi BO et al. J. Hum. Genet., 2007 Jan;52:280-3; Choi BO et al. J. Hum. Genet., 2007 Jan;52:280-3). In vitro functional assays have indicated this variant to result in reduced channel current, and dominant negative effect (Tristani-Firouzi M et al. J. Clin. Invest., 2002 Aug;110:381-8; Bendahhou S et al. J. Biol. Chem., 2003 Dec;278:51779-85; Bendahhou S et al. J. Biol. Chem., 2003 Dec;278:51779-85). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics RCV002483105 SCV002785124 pathogenic Andersen Tawil syndrome; Short QT syndrome type 3; Atrial fibrillation, familial, 9 2021-09-29 criteria provided, single submitter clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India RCV000157273 SCV004800833 pathogenic Andersen Tawil syndrome criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust RCV000058327 SCV000089847 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported in the following publications (PMID:11371347;PMID:12163457;PMID:17211524;PMID:17221872;PMID:22002906).
Blueprint Genetics RCV000157273 SCV000207004 pathogenic Andersen Tawil syndrome 2014-10-27 no assertion criteria provided clinical testing

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