ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1433C>T (p.Ser478Leu) (rs121912510)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000631649 SCV000752732 pathogenic Long QT syndrome 2017-09-18 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 818 of the KCNH2 protein (p.Ser818Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs121912510, ExAC 0.006%). This variant has been reported in several individuals affected with long QT syndrome being reported to be de novo in one of them (PMID: 10086971, 17088455, 18441445, 23158531, 26669661). ClinVar contains an entry for this variant (Variation ID: 14432). Experimental studies have shown that this missense change results in a KCNH2 protein that is not properly trafficked to the cell membrane and is not able to generate any current in vitro, and is unable to rescue the phenotype present in KCNH2-null zebrafish embryos (PMID: 10996323, 16432067, 23303164). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000631649 SCV000987593 likely pathogenic Long QT syndrome criteria provided, single submitter clinical testing
OMIM RCV000015513 SCV000035778 pathogenic Long QT syndrome 2 2000-09-15 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058123 SCV000089643 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:10086971;PMID:10996323;PMID:11222472;PMID:16432067;PMID:16831322;PMID:18441445). 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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