ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1744C>T (p.Arg582Cys) (rs121912508)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181815 SCV000234118 pathogenic not provided 2014-04-24 criteria provided, single submitter clinical testing p.Arg582Cys (CGC>TGC): c.1744 C>T in exon 7 of the HERG gene (NM_000238.2)The R582C mutation has been reported multiple times in association with LQTS and was not reported in at least 1,500 alleles from control individuals in these studies (Jongbloed R et al., 1999; Van Langen J et al., 2003; Hofman N et al., 2011; Tester D et al., 2005; Kapplinger J et al., 2009). R582C was identified by Jongbloed et al. in two Dutch families with LQTS (Jongbloed R et al., 1999). Van Langen et al. also reported the R582C mutation in two families from the Netherlands and Belgium with LQTS (Van Langen J et al., 2003). Similarly, Hofman et al. described the R582C as a recurrent LQTS mutation in the Netherlands, suggesting that R582C is a possible founder mutation in this population (Hofman N et al., 2011). A mutation at this same residue (R582L) and in nearby residues (M579T, I583V, G584R) have been reported in association with LQTS, supporting the functional importance of this residue and this region of the protein. Furthermore, R582C was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, R582C in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s).
Invitae RCV000537059 SCV000627434 pathogenic Long QT syndrome 2017-07-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 582 of the KCNH2 protein (p.Arg582Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs121912508, ExAC no frequency). This variant has been reported in many individuals and families affected with Long QT syndrome (LQTS) (PMID: 10220144, 22949429, 12566525, 18441445, 21350584), and in two individuals affected with LQTS plus a seizure phenotype (PMID: 19038855). ClinVar contains an entry for this variant (Variation ID: 14428). Experimental studies have shown that this missense change impairs protein trafficking and channel inactivation (PMID: 21376840). For these reasons, this variant has been classified as Pathogenic.
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.

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