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

dbSNP: rs199473384

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000157273	SCV005184761	pathogenic	Andersen Tawil syndrome	2024-05-13	criteria provided, single submitter	clinical testing	Variant summary: KCNJ2 c.653G>A (p.Arg218Gln) results in a conservative amino acid change located in the Inward rectifier potassium channel, C-terminal (IPR041647) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 252048 control chromosomes. c.653G>A has been reported in the literature in multiple individuals affected with Andersen-Tawil Syndrome (e.g. Plaster_2001, Tristani-Firouzi_2002, Haruna_2007, Choi_2007). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.652C>T, p.Arg218Trp), supporting the critical relevance of codon 218 to KCNJ2 protein function. Multiple publications report experimental evidence and indicate an impact on protein function (Tristani-Firouzi_2002, Seebohm_2012, Bendahhou_2003). The following publications have been ascertained in the context of this evaluation (PMID: 12796536, 17221872, 11371347, 12163457, 14522976, 22002906, 17211524). ClinVar contains an entry for this variant (Variation ID: 67585). Based on the evidence outlined above, the variant was classified as pathogenic.
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