ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000170971 SCV000842588 pathogenic not provided 2016-07-13 criteria provided, single submitter clinical testing
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).
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
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).
GeneReviews RCV000009478 SCV000243874 pathogenic Andersen Tawil syndrome 2015-08-06 no assertion criteria provided literature only
Invitae RCV000814909 SCV000955346 pathogenic Andersen Tawil syndrome; Short QT syndrome 3 2018-12-12 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.
OMIM RCV000009478 SCV000029696 pathogenic Andersen Tawil syndrome 2002-09-01 no assertion criteria provided literature only

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