Submissions for variant NM_000238.4(KCNH2):c.1744C>T (p.Arg582Cys)

dbSNP: rs121912508

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181815	SCV000234118	pathogenic	not provided	2020-11-10	criteria provided, single submitter	clinical testing	Reported as a potential founder mutation from the Netherlands (Hofman et al., 2011); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 14428; Landrum et al., 2016); Not observed in large population cohorts (Lek 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 results in impaired protein trafficking and channel inactivation (Fougere et al., 2011); This variant is associated with the following publications: (PMID: 10220144, 21376840, 15840476, 19716085, 21350584, 17088455, 9973011, 19038855, 12566525, 18441445, 17293393, 22949429, 32686758)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537059	SCV000627434	pathogenic	Long QT syndrome	2024-08-29	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 582 of the KCNH2 protein (p.Arg582Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with LQTS plus a seizure phenotype and Long QT syndrome (LQTS) (PMID: 10220144, 12566525, 18441445, 19038855, 21350584, 22949429). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14428). 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: 21376840). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002399326	SCV002712138	pathogenic	Cardiovascular phenotype	2024-01-22	criteria provided, single submitter	clinical testing	The c.1744C>T (p.R582C) alteration is located in exon 7 (coding exon 7) of the KCNH2 gene. This alteration results from a C to T substitution at nucleotide position 1744, causing the arginine (R) at amino acid position 582 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in individuals and families reported to have long QT syndrome (LQTS), or from LQTS cohorts, and has been described as a possible founder mutation in the Netherlands (Jongbloed, 1999; Nagaoka, 2008; Johnson, 2009; Hofman, 2011). This amino acid position is not well conserved in available vertebrate species. In in vitro studies, this variant has been reported to result in abnormal protein trafficking and channel function (Fougere, 2011; Perry, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000057970	SCV004848873	likely pathogenic	Congenital long QT syndrome	2022-11-30	criteria provided, single submitter	clinical testing	The p.Arg582Cys (c.1744C>T) variant in KCNH2 has been reported in 17 individuals with Long QT Syndrome (Wilde 1999 PMID: 9973011, Tester 2005 PMID: 15840476, Tan 2006 PMID: 17088455, Nemec 2003 PMID: 12877697, Nagaoka 2008 PMID: 18441445, Lupoglazoff 2001 PMID: 11222472, Kapplinger 2009 PMID: 19716085, Jongbloed 1999 PMID: 10220144, Hofman 2011 PMID: 21350584). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 29467). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein trafficking and function (Tseng 2007 PMID: 17293393, Fougere 2011 PMID: 21376840); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Long QT Syndrome. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP3, PS3_Supporting.
OMIM	RCV000015509	SCV000035774	pathogenic	Long QT syndrome 2	1999-01-01	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057970	SCV000089490	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:10220144;PMID:11222472;PMID:12566525;PMID:12877697;PMID:15840476;PMID:19716085;PMID:19841300;PMID:21376840). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000181815	SCV001741590	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000181815	SCV001958562	pathogenic	not provided		no assertion criteria provided	clinical testing