Submissions for variant NM_000891.3(KCNJ2):c.934C>T (p.Arg312Cys)

dbSNP: rs199473389

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000443262	SCV000515710	likely pathogenic	not provided	2019-08-22	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22806368, 15723059, 19862833, 12796536, 25284084)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001055449	SCV001219842	pathogenic	Andersen Tawil syndrome; Short QT syndrome type 3	2023-04-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 312 of the KCNJ2 protein (p.Arg312Cys). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNJ2 function (PMID: 12086641). 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. ClinVar contains an entry for this variant (Variation ID: 67594). This missense change has been observed in individuals with clinical features of Andersen-Tawil syndrome (PMID: 12796536, 15911703, 22806368, 25284084). This variant is present in population databases (rs199473389, gnomAD 0.0009%).
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV002054905	SCV002320711	pathogenic	Andersen Tawil syndrome	2021-11-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003390761	SCV004110087	likely pathogenic	KCNJ2-related disorder	2023-06-27	criteria provided, single submitter	clinical testing	The KCNJ2 c.934C>T variant is predicted to result in the amino acid substitution p.Arg312Cys. This variant was reported in multiple individual with Andersen syndrome (Donaldson et al. 2003. PubMed ID: 12796536; Zhang et al. 2005. PubMed ID: 15911703; Tan et al. 2012. PubMed ID: 22806368; Nagamine et al. 2014. PubMed ID: 25284084). Functional studies found this variant affects KCNJ2 function (Donaldson et al. 2003. PubMed ID: 12796536). This variant has been interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/67594/). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-68172114-C-T). This variant is interpreted as likely pathogenic.
Ambry Genetics	RCV004992005	SCV005602530	likely pathogenic	Cardiovascular phenotype	2024-11-01	criteria provided, single submitter	clinical testing	The p.R312C variant (also known as c.934C>T), located in coding exon 1 of the KCNJ2 gene, results from a C to T substitution at nucleotide position 934. The arginine at codon 312 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in association with KCNJ2 - related disease (Donaldson MR et al. Neurology, 2003 Jun;60:1811-6; Zhang L et al. Circulation, 2005 May;111:2720-6; Tan SV et al. Muscle Nerve, 2012 Aug;46:193-203; Limberg MM et al. Basic Res Cardiol, 2013 May;108:353; Yuan JH et al. Front Neurol, 2023 Jan;14:1078195). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant was also shown to have diminished current compared to the wild type in a heterozygous expression assay (Lopes CM et al. Neuron, 2002 Jun;34:933-44). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058339	SCV000089859	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported in the following publications (PMID:12796536).
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV002054905	SCV002600034	pathogenic	Andersen Tawil syndrome	2022-04-12	no assertion criteria provided	research