ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.2162C>T (p.Pro721Leu) (rs199472986)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000458802 SCV000543427 likely pathogenic Long QT syndrome 2018-05-29 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 721 of the KCNH2 protein (p.Pro721Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (rs199472986, ExAC no frequency). This variant has been reported in at least one individual affected with long QT syndrome (PMID: 15840476, 19841300, 22949429, 26669661). ClinVar contains an entry for this variant (Variation ID: 67371). Experimental studies have shown that this missense change leads to a trafficking-deficient KCNH2 protein that is unable to be corrected in vitro (PMID: 25417810). In summary, this variant is absent from population databases, has been observed in at least one patient with long QT syndrome, and has been shown to have a deleterious functional effect. In the absence of confirmed segregation evidence, at this time this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000058091 SCV001362894 likely pathogenic Congenital long QT syndrome 2019-02-06 criteria provided, single submitter clinical testing Variant summary: The variant, KCNH2 c.2162C>T (p.Pro721Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 36208 control chromosomes (gnomAD) and has been reported in the literature in individuals affected with Long-QT syndrome (Giudicessi_2012, Itoh_2016, Kapa_2009). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and state that the missense change leads to a trafficking deficient protein which cannot be corrected in their in vitro studies (Anderson _2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058091 SCV000089611 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:15840476;PMID:19841300). 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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