Submissions for variant NM_000891.3(KCNJ2):c.199C>T (p.Arg67Trp)

dbSNP: rs104894580

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170971	SCV000223534	pathogenic	not provided	2022-04-20	criteria provided, single submitter	clinical testing	Observed in multiple unrelated patients from different ethnic backgrounds with KCNJ2-related disorders referred for genetic testing at GeneDx and in published literature (Andelfinger et al., 2002; Donaldson et al., 2003; Chun et al., 2004; Davies et al., 2005; Haruna et al., 2007; Kimura et al., 2012; Tan et al., 2012; Jabbari et al., 2013; Lieve et al., 2013; Song et al., 2016); 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; Published functional studies demonstrate the variant alters channel function (Donaldson et al., 2003; Andelfinger et al., 2002); This variant is associated with the following publications: (PMID: 11841151, 22589293, 15851159, 24561538, 23631430, 24025405, 17221872, 16217063, 22806368, 12796536, 20301441, 11861044, 27145478, 31068157, 31509255, 31567646, 23867365, 20713726, 15911703, 26582918, 32499698, 12148092)
Athena Diagnostics	RCV000170971	SCV000842588	pathogenic	not provided	2016-07-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763415	SCV000894148	pathogenic	Andersen Tawil syndrome; Short QT syndrome type 3; Atrial fibrillation, familial, 9	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814909	SCV000955346	pathogenic	Andersen Tawil syndrome; Short QT syndrome type 3	2024-01-28	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 67 of the KCNJ2 protein (p.Arg67Trp). 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: 12148092, 12796536, 17221872, 22589293, 22806368, 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: 8923). 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: 12148092, 20713726). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000954	SCV001158053	pathogenic	not specified	2018-12-05	criteria provided, single submitter	clinical testing	The KCNJ2 c.199C>T; p.Arg67Trp variant (rs104894580), is reported in the literature in multiple individuals and families affected with Andersen-Tawil syndrome (ATS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and isolated periodic paralysis (Andelfinger 2002, Chun 2004, Donaldson 2003, Haruna 2007, Jabbari 2013, Kimura 2012, Lieve 2013, Tan 2012). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 8923), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 67 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show loss of channel function, dominant negative effects, and decreased PIP2 binding that inhibits channel function (Andelfinger 2002, Donaldson 2003). Based on available information, the p.Arg67Trp variant is considered to be pathogenic. References: Andelfinger G et al. KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am J Hum Genet. 2002 Sep;71(3):663-8. Chun TU et al. Polymorphic ventricular tachycardia and KCNJ2 mutations. Heart Rhythm. 2004 Jul;1(2):235-41. Donaldson MR et al. PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome. Neurology. 2003 Jun 10;60(11):1811-6. Haruna Y et al. Genotype-phenotype correlations of KCNJ2 mutations in Japanese patients with Andersen-Tawil syndrome. Hum Mutat. 2007 Feb;28(2):208. Jabbari J et al. New exome data question the pathogenicity of genetic variants previously associated with catecholaminergic polymorphic ventricular tachycardia. Circ Cardiovasc Genet. 2013 Oct;6(5):481-9. Kimura H et al. Phenotype variability in patients carrying KCNJ2 mutations. Circ Cardiovasc Genet. 2012 Jun;5(3):344-53. Lieve KV et al. Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. Genet Test Mol Biomarkers. 2013 Jul;17(7):553-61. Tan SV et al. Membrane dysfunction in Andersen-Tawil syndrome assessed by velocity recovery cycles. Muscle Nerve. 2012 Aug;46(2):193-203.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000170971	SCV001446657	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV000009478	SCV002038508	pathogenic	Andersen Tawil syndrome	2021-12-17	criteria provided, single submitter	clinical testing	We observed the p.R67W variant in a 29-y.o. female proband, who experienced a cardiac arrest and had a cardioverter-defibrillator implanted for secondary prophylaxis of sudden cardiac death. Extra-cardiac phenotype had included short stature, low-set and rotated ears, hypertelorism, epicanthus, small mandibulae and chin, clinodactyly of the IV-V finders, small hands, and feet, and mild scoliosis. Its effect of p.R67W variatn is described in in vitro studies (PS3 criteria); the variant is absent in large databases (PM2 criteria). The variant was not detected in proband's parents (PM6 criteria). Various in silico tools predict the variant to be deleterious (PP3 criteria), and the p.R67W variant was described previously as pathogenic (PP5 criteria). Based on all the criteria, we consider p.R67W variant to be pathogenic.
Ambry Genetics	RCV002415408	SCV002717713	pathogenic	Cardiovascular phenotype	2020-03-26	criteria provided, single submitter	clinical testing	The p.R67W pathogenic mutation (also known as c.199C>T), located in coding exon 1 of the KCNJ2 gene, results from a C to T substitution at nucleotide position 199. The arginine at codon 67 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals with Andersen-Tawil syndrome, including de novo occurrence as well as strong segregation with disease in affected families (Andelfinger G et al. Am. J. Hum. Genet., 2002 Sep;71:663-8; Davies NP et al. Neurology, 2005 Oct;65:1083-9; Haruna Y et al. Hum. Mutat., 2007 Feb;28:208; Delannoy E et al. Europace, 2013 Dec;15:1805-11). This mutation has also been reported in long QT syndrome and primary periodic paralysis cohorts (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Luo S et al. BMC Neurol, 2019 May;19:92). Limited functional studies demonstrated significant impact on potassium channel function (Andelfinger G et al. Am. J. Hum. Genet., 2002 Sep;71:663-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000009478	SCV000029696	pathogenic	Andersen Tawil syndrome	2002-09-01	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058294	SCV000089814	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported in the following publications (PMID:12148092;PMID:12796536;PMID:15851159;PMID:16217063;PMID:17221872).
GeneReviews	RCV000009478	SCV000243874	not provided	Andersen Tawil syndrome		no assertion provided	literature only
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV000009478	SCV002600043	pathogenic	Andersen Tawil syndrome	2022-04-12	no assertion criteria provided	research