Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000181800 | SCV000234103 | pathogenic | not provided | 2020-02-11 | criteria provided, single submitter | clinical testing | Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 67220; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant alters the activation and deactivation kinetics, as well as voltage-dependence of inactivation of the potassium channel (Nakajiima et al., 1999); This variant is associated with the following publications: (PMID: 31844156, 10690305, 23303164, 9600240, 15840476, 18441445, 18752142, 19716085, 19694797, 21308345, 22949429, 15545400, 16432067, 11468227, 10987356, 17905336, 19841300, 30847666) |
| Labcorp Genetics |
RCV000470519 | SCV000543469 | pathogenic | Long QT syndrome | 2024-01-15 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 534 of the KCNH2 protein (p.Arg534Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 9600240, 11668638, 18441445, 21308345, 22949429). ClinVar contains an entry for this variant (Variation ID: 67220). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 10690305, 16432067, 23303164). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002399420 | SCV002709150 | pathogenic | Cardiovascular phenotype | 2020-06-26 | criteria provided, single submitter | clinical testing | The p.R534C pathogenic mutation (also known as c.1600C>T), located in coding exon 7 of the KCNH2 gene, results from a C to T substitution at nucleotide position 1600. The arginine at codon 534 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the S4 domain. This mutation has been detected in several unrelated individuals with long QT syndrome as well as in individuals from multiple LQTS cohorts, and has been reported to segregate with disease in families (Itoh T et al. Hum. Genet., 1998 Apr;102:435-9; Nakajima T et al. Cardiovasc. Res., 1999 Nov;44:283-93; Hayashi K et al. Jpn Heart J, 2000 May;41:399-404; Chung SK et al. Heart Rhythm, 2007 Oct;4:1306-14; Ernesto C et al. Arq. Bras. Cardiol., 2011 Mar;96:172-8; Giudicessi JR et al. Circ Cardiovasc Genet, 2012 Oct;5:519-28; Seethala S et al. J Am Heart Assoc, 2015 Dec;4). In addition, in vitro and in vivo functional assays have indicated this variant to result in deficient protein trafficking and/or altered ion channel function (Nakajima T et al. Cardiovasc. Res., 1999 Nov;44:283-93; Anderson CL et al. Circulation, 2006 Jan;113:365-73; Jou CJ et al. Circ. Res., 2013 Mar;112:826-30; Mesquita FCP et al. Sci Rep, 2019 12;9:19203). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Cardiovascular Biomedical Research Unit, |
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. |