ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1477T>C (p.Tyr493His)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000815444 SCV000955897 uncertain significance Long QT syndrome 2018-07-12 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 493 of the KCNH2 protein (p.Tyr493His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual referred for genetic testing for long QT syndrome (PMID: 23631430). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. The observation of one or more missense substitutions at this codon (p.Tyr493Cys and p.Tyr493Phe) in affected individuals suggests that this may be a clinically significant residue (PMID: 22949429, 14998624, 19668779). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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