ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1372A>T (p.Ile458Phe) (rs374303744)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000541352 SCV000627423 uncertain significance Long QT syndrome 2017-07-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 458 of the KCNH2 protein (p.Ile458Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a KCNH2-related disease. This variant identified in the KCNH2 gene is located in the transmembrane S2 region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNH2-topology. It is unclear how this variant impacts the function of this protein. 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on KCNH2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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