Submissions for variant NM_000891.3(KCNJ2):c.244C>T (p.Arg82Trp)

dbSNP: rs199473373

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001703967	SCV000223539	pathogenic	not provided	2023-09-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate variant has a dominant negative effect on channel current when co-expressed with wild-type (Eckhardt et al., 2007; Kimura et al., 2012; Le Tanno et al., 2021); 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: 17341397, 24025405, 23631430, 22589293, 24561538, 28336205, 31737537, 34899860, 16818210)
Invitae	RCV000535797	SCV000637450	pathogenic	Andersen Tawil syndrome; Short QT syndrome type 3	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 82 of the KCNJ2 protein (p.Arg82Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with catecholaminergic polymorphic ventricular tachycardia (PMID: 16818210). ClinVar contains an entry for this variant (Variation ID: 67568). 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) performed at Invitae indicates that this missense variant is expected to disrupt KCNJ2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KCNJ2 function (PMID: 17341397, 22589293). This variant disrupts the p.Arg82 amino acid residue in KCNJ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16217063, 22589293, 22806368, 23644778). 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.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV001258373	SCV001435344	pathogenic	Andersen Tawil syndrome	2020-08-14	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Region Ostergotland	RCV001258373	SCV001977086	pathogenic	Andersen Tawil syndrome	2020-03-04	criteria provided, single submitter	clinical testing	PS4, PM2, PM5, PP3, PP5
Ambry Genetics	RCV002453375	SCV002736802	pathogenic	Cardiovascular phenotype	2019-03-29	criteria provided, single submitter	clinical testing	The p.R82W pathogenic mutation (also known as c.244C>T), located in coding exon 1 of the KCNJ2 gene, results from a C to T substitution at nucleotide position 244. The arginine at codon 82 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in Andersen-Tawil syndrome (ATS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and long QT syndrome (LQTS) cohorts (Tester DJ et al. Heart Rhythm, 2006 Jul;3:800-5; Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Kimura H et al. Circ Cardiovasc Genet, 2012 Jun;5:344-53; Kostera-Pruszczyk A et al. Muscle Nerve, 2015 Feb;51:192-6; Rhodes T et al. Card Electrophysiol Clin, 2015 Sep;7:479-86; Krych M et al. J Cardiol, 2017 Nov;70:504-510). Functional studies indicate that this variant has a dominant negative impact on current density (Eckhardt LL et al. Heart Rhythm, 2007 Mar;4:323-9; Kimura H et al. Circ Cardiovasc Genet, 2012 Jun;5:344-53). In addition, a likely pathogenic alteration in the same codon (p.R82Q) has been described (Davies NP et al. Neurology. 2005 Oct 11;65(7):1083-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058305	SCV000089825	not provided	Ventricular tachycardia		no assertion provided	literature only	This variant has been reported as associated with Ventricular tachycardia in the following publications (PMID:16818210;PMID:17341397). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678808	SCV000804992	pathogenic	Supraventricular tachycardia	2016-10-11	no assertion criteria provided	clinical testing