ClinVar Miner

Submissions for variant NM_000891.2(KCNJ2):c.199C>T (p.Arg67Trp) (rs104894580)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170971 SCV000223534 pathogenic not provided 2018-10-12 criteria provided, single submitter clinical testing The R67W pathogenic variant in the KCNJ2 gene has previously been reported in association with Andersen-Tawil syndrome(ATS), polymorphic ventricular tachycardia, catecholaminergic polymorphic ventricular tachycardia (CPVT), andisolated periodic paralysis (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). Andelfinger et al. (2002) observedR67W segregation with disease in 41 members of a kindred affected with ATS. Haruna et al. (2007) reported R67Win three individuals affected with ATS in one family, and also reported another variant affecting the same residue(R67Q) in an individual with ATS. Chun et al. (2004) identified R67W in two unrelated individuals withpolymorphic VT or bidirectional VT, similar to a CPVT phenotype. In addition, Jabbari et al. (2013) observedR67W segregated with disease in a family with CPVT. Kimura et al. (2012) reported R67W in one male individualwhose only symptom was periodic paralysis. The R67W variant was found to have occurred apparently de novo intwo patients with ATS (Davies et al., 2005; Donaldson et al., 2003). The R67W variant is a non-conservative amino acid substitution, which is likely to impact secondary proteinstructure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a positionthat is conserved across species. Functional studies by Donaldson et al. (2003) demonstrated that the R67W variantaffects a hot-spot residue involved in binding phosphatidyl-inositol 4,5-biphosphate (PIP2), which decreases itsaffinity for PIP2 and inhibits channel function when altered. In addition, Andelfinger et al. (2002) demonstrated withelectrophysiological studies in Xenopus oocytes that the presence of R67W significantly alters channel function andhas a dominant-negative effect on co-expressed wild-type channels. Furthermore, R67W is not observed in largepopulation cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Athena Diagnostics Inc 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 3; Atrial fibrillation, familial, 9 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000814909 SCV000955346 pathogenic Andersen Tawil syndrome; Short QT syndrome 3 2019-06-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 67 of the KCNJ2 protein (p.Arg67Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with Andersen-Tawil syndrome (PMID: 12796536), to segregate with this disease in families (PMID: 12148092, 17221872), and observed in unrelated affected individuals (PMID: 22806368, 23867365, 22589293). ClinVar contains an entry for this variant (Variation ID: 8923). Experimental studies have shown that this missense change results in a complete loss of channel 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.
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 pathogenic Andersen Tawil syndrome 2015-08-06 no assertion criteria provided literature only

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