ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1778T>A (p.Ile593Lys) (rs28928904)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000557658 SCV000627436 pathogenic Long QT syndrome 2017-07-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with lysine at codon 593 of the KCNH2 protein (p.Ile593Lys). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and lysine. This variant is not present in population databases (rs28928904, ExAC no frequency). This variant has been reported in an individual with long QT syndrome (PMID: 21956039), as well as in an individual referred for long QT syndrome genetic testing (PMID: 19716085). In addition, this variant has been demonstrated to segregate with long QT syndrome in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 67269). This variant identified in the KCNH2 gene is located in the transmembrane spanning S5/pore region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit Experimental studies have shown that this missense change leads to defecting protein trafficking (PMID: 25417810). A different missense substitution at this codon (p.Ile593Arg) has been determined to be pathogenic (PMID: 25417810, 9694858, 23303164, 10973849, 8635257). This suggests that the isoleucine 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 RCV000057984 SCV000089504 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:19716085). 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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