ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1853C>T (p.Thr618Ile) (rs199472947)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001376739 SCV001573900 likely pathogenic Long QT syndrome 2017-05-10 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 618 of the KCNH2 protein (p.Thr618Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (rs199472947, ExAC no frequency). This variant has been reported in a single family affected with short QT syndrome (PMID: 21130771). Experimental studies have shown that this missense change reduces KCNH2 inactivation, resulting in a gain of function of the channel (PMID: 21130771, 23300672, 23471968). In summary, this variant is a rare missense change that has been shown to disrupt protein function and to segregate with disease in a single family. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058015 SCV000089535 not provided short QT syndrome no assertion provided literature only This variant has been reported as associated with Short QT syndrome in the following publications (PMID:21130771). 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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