ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.1887C>A (p.Asn629Lys)

dbSNP: rs41307295
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001854201 SCV002303944 likely pathogenic Long QT syndrome 2021-09-08 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 629 of the KCNH2 protein (p.Asn629Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with long QT syndrome (PMID: 10517660; Invitae). ClinVar contains an entry for this variant (Variation ID: 67317). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this variant affects KCNH2 function (PMID: 10517660, 25417810). This variant disrupts the p.Asn629 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10973849, 16432067, 17905336, 19841300). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust RCV000058036 SCV000089556 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:10517660). 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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