ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1447C>T (p.Arg483Trp) (rs199473538)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000234770 SCV000283973 pathogenic Long QT syndrome 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 823 of the KCNH2 protein (p.Arg823Trp). 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 reported in numerous individuals and families affected with long QT syndrome  (PMID: 10973849, 11854117, 16831322, 19695459, 19716085, 23158531, 23631430). Experimental studies have shown that this missense change is deficient in trafficking and is unable to rescue the loss of KCNH2 in an experimental animal system (PMID: 11741928, 16432067, 23303164). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000058126 SCV000731561 likely pathogenic Congenital long QT syndrome 2017-06-12 criteria provided, single submitter clinical testing The p.Arg823Trp variant in KCNH2 has been reported in >10 individuals with long QT syndrome (Splawski 2000, Moss 2002, Kapplinger 2009, Nishio 2009, Crotti 2012 , Lieve 2013, Itoh 2016, ClinVar Variation ID 67402) and has also been reported in ClinVar (Variation ID 67402). In vitro functional studies provide some eviden ce that the p.Arg823Trp variant may impact protein function (Ficker 2002, Roti 2 002, Anderson 2006). The p.Arg823Trp variant has also been identified in 1/11170 2 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gno mad.broadinstitute.org/; dbSNP rs199473538). Computational prediction tools and conservation analysis suggest that the variant may impact the protein, though th is information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical signifi cance, the p.Arg823Trp variant is likely pathogenic.
Ambry Genetics RCV000618449 SCV000737553 likely pathogenic Cardiovascular phenotype 2016-06-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058126 SCV000089646 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:10973849;PMID:11854117;PMID:16432067;PMID:16831322;PMID:19716085;PMID:11741928). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786142 SCV000924811 pathogenic not provided 2016-02-17 no assertion criteria provided provider interpretation

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