ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1909G>A (p.Glu637Lys) (rs199472968)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000691309 SCV000819084 pathogenic Long QT syndrome 2018-04-26 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 637 of the KCNH2 protein (p.Glu637Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with long QT syndrome (PMID: 12062363, 12808265). ClinVar contains an entry for this variant (Variation ID: 67329). Experimental studies have shown that this missense change disrupts protein trafficking, abolishing channel currents and causing dominant negative suppression of wild type channels (PMID: 12062363, 25417810, 23022675). A different missense substitution at this codon (p.Glu637Gly) has been determined to be pathogenic (PMID: 21109023, 21216356, 25417810). This suggests that the glutamic acid residue is critical for KCNH2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058048 SCV000089568 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:12062363). 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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