ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1755G>C (p.Trp585Cys) (rs199473430)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000705565 SCV000834566 likely pathogenic Long QT syndrome 2018-03-16 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 585 of the KCNH2 protein (p.Trp585Cys). 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 reported in an individual affected with long QT syndrome (Invitae). A different variant (c.1755G>T) giving rise to the same protein effect observed here (p.Trp585Cys) has been reported in an individual affected with long QT syndrome (PMID: 10973849), indicating that this residue may be critical for protein function. Experimental studies have shown that this missense change causes a disruption of channel function, misfolding of the KCNH2 protein and trafficking-deficiency (PMID: 12407082, 25417810). 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.

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