ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1750G>T (p.Gly584Trp) (rs794728397)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619449 SCV000737625 uncertain significance Cardiovascular phenotype 2016-07-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000631724 SCV000752812 uncertain significance Long QT syndrome 2017-11-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with tryptophan at codon 924 of the KCNH2 protein (p.Gly924Trp). The glycine residue is weakly conserved and there is a large physicochemical difference between glycine and tryptophan. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with KCNH2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Different missense substitutions at this codon (p.Gly924Glu, p.Gly924Ala) have been reported in individuals affected with long QT syndrome (PMID: 19716085). This suggests that missense substitutions at this position may be pathogenic. 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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