ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.194C>G (p.Thr65Ser) (rs878853772)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000231224 SCV000283969 uncertain significance Long QT syndrome 2016-02-17 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 65 of the KCNH2 protein (p.Thr65Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Thr65Pro) is reported to be deleterious (PMID: 12354768, 15840476, 16922724, 21661061). This suggests that the threonine residue is important for KCNH2 protein function. In summary, this is a novel missense change with uncertain impact on protein function located within a codon important for KCNH2 protein function. In the absence of genetic and/or functional data on this variant in the literature, at this point, it has been classified as a Variant of Uncertain Significance.

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