Submissions for variant NM_000891.3(KCNJ2):c.652C>T (p.Arg218Trp)

dbSNP: rs104894578

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170982	SCV000223545	pathogenic	not provided	2023-05-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies demonstrate a damaging effect: the variant causes a loss of function and a dominant negative effect on channel function when expressed with the wild-type protein (Plaster et al., 2001; Lange et al. 2003; Caballero et al., 2010); Also known as Kir2.1; This variant is associated with the following publications: (PMID: 12163457, 17568571, 17211524, 23631430, 20647529, 11371347, 25415519, 23867365, 15269659, 17119796, 18554214, 28501311, 12796536, 17221872, 22589293, 29093808, 15852530, 16217063, 17399642, 22581653, 28024840, 31068157, 31567646, 34008892, 35460302, 33057326, 20713726, 12909315)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000684775	SCV000285639	pathogenic	Andersen Tawil syndrome; Short QT syndrome type 3	2023-07-12	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 8919). 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. Experimental studies have shown that this missense change affects KCNJ2 function (PMID: 12909315, 17119796, 17568571). For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with Andersen-Tawil syndrome (PMID: 12796536, 17119796, 17221872, 22589293). 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 218 of the KCNJ2 protein (p.Arg218Trp).
Athena Diagnostics	RCV000170982	SCV000842589	pathogenic	not provided	2018-05-10	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000009474	SCV000928340	pathogenic	Andersen Tawil syndrome	2018-01-18	criteria provided, single submitter	clinical testing	PM2, PM5, PP2, PP3, PP4, PP5
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000170982	SCV001447312	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Genetics Laboratory, Department of Biology, Semnan University	RCV000009474	SCV002569118	pathogenic	Andersen Tawil syndrome	2020-01-06	criteria provided, single submitter	case-control	The identified mutation leads to the substitution of Arginine 218 with Tryptophan (R218W) in the KCNJ2 protein. Hence, this substitution alters the amino acid sequence and leads to a missense mutation at position 218 with possible increased function in the mutated protein.
Center of Excellence for Medical Genomics, Chulalongkorn University	RCV000009474	SCV002583253	likely pathogenic	Andersen Tawil syndrome	2022-10-05	criteria provided, single submitter	research
Ambry Genetics	RCV004018605	SCV003745282	pathogenic	Cardiovascular phenotype	2024-07-11	criteria provided, single submitter	clinical testing	The p.R218W pathogenic mutation (also known as c.652C>T), located in coding exon 1 of the KCNJ2 gene, results from a C to T substitution at nucleotide position 652. The arginine at codon 218 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported in multiple individuals with features consistent with Andersen-Tawil syndrome (ATS), including de novo occurrences, has been reported to segregate with disease features in families, and has shown intrafamilial phenotypic variability (Plaster NM et al. Cell. 2001 May;105(4):511-9; Donaldson MR et al. Neurology. 2003 Jun;60(11):1811-6; Tengan CH et al. Arq Neuropsiquiatr. 2006 Sep;64(3A):582-4; Haruna Y et al. Hum Mutat. 2007 Feb;28(2):208; Kimura H et al. Circ Cardiovasc Genet. 2012 Jun;5(3):344-53; Lefter S et al. J Clin Neuromuscul Dis. 2014 Dec;16(2):79-82; Ardissone A et al. Neuromuscul Disord. 2017 Mar;27(3):294-297; Villar-Quiles RN et al. Eur J Neurol. 2022 Aug;29(8):2398-2411). Another variant at the same codon, p.R218Q (c.653G>A), has also been reported in association with ATS (Plaster NM et al. Cell, 2001 May;105:511-9). In assays testing KCNJ2 function, this variant showed functionally abnormal results (Plaster NM. Cell. 2001 May;105(4):511-9; Lange PS. Cardiovasc Res. 2003 Aug;59(2):321-7). 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 is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Revvity Omics, Revvity	RCV000170982	SCV003820874	pathogenic	not provided	2022-04-28	criteria provided, single submitter	clinical testing
OMIM	RCV000009474	SCV000029692	pathogenic	Andersen Tawil syndrome	2001-05-18	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058326	SCV000089846	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:12796536;PMID:15852530;PMID:16217063;PMID:17074642;PMID:17119796;PMID:17221872;PMID:17399642;PMID:18554214;PMID:20647529).
GeneReviews	RCV000009474	SCV000243876	not provided	Andersen Tawil syndrome		no assertion provided	literature only
Clinical Genetics, Academic Medical Center	RCV000170982	SCV001917732	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000170982	SCV001951246	pathogenic	not provided		no assertion criteria provided	clinical testing