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 2020-05-21 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25820318, 25417810, 23303164, 16414944, 21536673, 29725305, 32475984)
Invitae RCV000823889 SCV000964760 likely pathogenic Long QT syndrome 2019-08-17 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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