ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1600C>T (p.Arg534Cys) (rs199472916)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181800 SCV000234103 pathogenic not provided 2018-01-26 criteria provided, single submitter clinical testing The R534C pathogenic variant in the KCNH2 gene has been published numerous times in association with LQTS (Itoh et al., 1998; Hayashi et al., 2000; Tester et al., 2005; Chung et al., 2007; Nagaoka et al., 2008; Berge et al., 2008; Omichi et al., 2010; Ernesto et al., 2011; Giudicessi J et al., 2012). Itoh et al. (1998) and Ernesto et al. (2011) both reported that the R534C variant segregated with LQTS in multiple individuals from two unrelated families. The R534C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This variant occurs at a residue located within the S4 transmembrane voltage sensor of the potassium channel at a position that is highly conserved across species. Functional studies demonstrated that R534C alters the activation and deactivation kinetics, as well as voltage-dependence of inactivation of the potassium channel (Nakajiima et al., 1999). Furthermore, the R534C pathogenic variant is not observed in large population cohorts (Lek et al., 2016).
Invitae RCV000470519 SCV000543469 pathogenic Long QT syndrome 2019-07-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 534 of the KCNH2 protein (p.Arg534Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs199472916, ExAC no frequency). This variant has been reported in several individuals and families affected with long QT syndrome (PMID: 22949429, 18441445, 9600240, 11668638, 21308345). ClinVar contains an entry for this variant (Variation ID: 67220). Experimental studies using model organisms have shown that this variant affects activation and repolarization of the KCNH2 channel (PMID: 16432067, 23303164, 10690305). For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057929 SCV000089449 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:9600240;PMID:10690305;PMID:10987356;PMID:11468227;PMID:15840476;PMID:16432067;PMID:16831322;PMID:17905336;PMID:18441445;PMID:18752142;PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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