ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1704G>C (p.Trp568Cys) (rs199472926)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000689953 SCV000817626 likely pathogenic Long QT syndrome 2018-08-08 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 568 of the KCNH2 protein (p.Trp568Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with long QT syndrome in a family (Invitae), and has been observed in several individuals affected with the disease (PMID: 11222472, 17905336, 27920829). ClinVar contains an entry for this variant (Variation ID: 67243). Experimental studies have shown that this missense change decreases protein trafficking (PMID: 25417810). A different variant (c.1704G>T) giving rise to the same protein effect observed here (p.Trp568Cys) has been reported in an individual affected with long QT syndrome (PMID: 16265869), indicating that this residue may be critical for protein function. 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 RCV000057954 SCV000089474 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:16265869;PMID:17224687;PMID:17905336). 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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