ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.128A>G (p.Tyr43Cys) (rs199472836)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181926 SCV000234229 pathogenic not provided 2018-12-11 criteria provided, single submitter clinical testing The Y43C pathogenic variant in the KCNH2 gene has been reported in association with LQTS (Napolitano et al., 2005). Y43C is not observed in large population cohorts (Lek et al., 2016). The Y43C variant results in a non-conservative amino acid substitution and in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, this variant is located in the PAS domain, which is thought to participate in the regulation of channel function (Harley et al., 2012). Functional studies suggest that Y43C causes deficient protein trafficking to the cell membrane that is at least partially correctable at lower temperatures (Gianulis et al., 2011; Anderson et al., 2014; Kanner et al., 2018). In addition, an in vivo assay measuring normal repolarization rescue in KCNH2-knockdown embryonic zebrafish demonstrated that Y43C resulted in a significantly lower degree of repolarization rescue compared to wild-type (Jou et al., 2013). Lastly, variants in the same residue (Y43D) and a nearby residue (C44Y) have been reported in Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this region of the protein.
Invitae RCV000823889 SCV000964760 likely pathogenic Long QT syndrome 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 43 of the KCNH2 protein (p.Tyr43Cys). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with long QT syndrome in a family (Invitae) and has been reported in unrelated individuals affected with this disease (PMID: 16414944, 23098067). ClinVar contains an entry for this variant (Variation ID: 67182). Experimental studies have shown that this missense change results in abnormal protein trafficking, immature form of the channel and absence of measurable hERG current (PMID: 25417810, 23303164, 21536673, 23721480, 29725305). This variant disrupts the p.Tyr43 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 19419905, 18441445), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057889 SCV000089409 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;PMID:21536673). 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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