ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1711A>G (p.Ile571Val) (rs199472928)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000436135 SCV000516645 pathogenic not provided 2017-05-04 criteria provided, single submitter clinical testing The I571V variant in the KCNH2 gene has been reported in one individual with LQTS and was absent in800 control chromosomes (Napolitano et al., 2005). Functional studies have shown that the I571V variant results in deficient sodium channel trafficking (Anderson et al., 2014). Although I571V results in aconservative amino acid substitution, it occurs at a position that is conserved across species. Missensevariants affecting the same residue (I571L, I571M) and in nearby residues (W568R, W568C, Y569H,Y569C, G572R, G572C) have been reported in HGMD in association with LQTS (Stenson P et al., 2014),further supporting the functional importance of this region of the protein. Furthermore, the I571V substitutionwas not observed in approximately 6,500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, I571V in the KCNH2 gene is interpreted as a pathogenic variant.
Invitae RCV000556890 SCV000627433 uncertain significance Long QT syndrome 2017-08-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 571 of the KCNH2 protein (p.Ile571Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (rs199472928, ExAC no frequency). This variant has been reported in an individual affected with Romano-Ward syndrome (PMID: 16414944). ClinVar contains an entry for this variant (Variation ID: 67247). Experimental studies have shown that this missense change disrupts trafficking of the KCNH2 protein (PMID: 25417810). In summary, this variant is a rare missense change that disrupts protein function in vitro. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057958 SCV000089478 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16414944). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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