ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1478A>G (p.Tyr493Cys) (rs199472911)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000412722 SCV000490936 likely pathogenic not provided 2016-03-03 criteria provided, single submitter clinical testing The Y493C likely pathogenic variant in the KCNH2 gene has been reported previously in at leastthree unrelated individuals with LQTS and was absent in at least 2,600 control alleles (Lupoglazoff etal., 2004; Kapplinger et al., 2009; Kapa et al., 2009; Giudicessi et al., 2012). Lupoglazoff et al. (2004)reported that Y493C occured de novo in an individual with neonatal LQTS and fetal bradycardia.Additionally, the Y493C variant was not observed in approximately 6,500 individuals of European andAfrican American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a commonbenign variant in these populations. The Y493C variant is a non-conservative amino acid substitution,which is likely to impact secondary protein structure as these residues differ in polarity, charge, sizeand/or other properties. Moreover, this substitution occurs at a position that is conserved acrossspecies. Consequently, in silico analysis predicts this variant is probably damaging to the proteinstructure/function. Therefore, this variant is likely pathogenic.
Invitae RCV001207034 SCV001378371 likely pathogenic Long QT syndrome 2019-10-11 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 493 of the KCNH2 protein (p.Tyr493Cys). The tyrosine residue is highly 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 be de novo in an individual affected with long QT syndrome (PMID: 14998624) and has been observed in other individuals affected with this disease (PMID: 22949429, 19716085). ClinVar contains an entry for this variant (Variation ID: 67206). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Tyr493 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been observed in individuals with KCNH2-related conditions (PMID: 19668779), 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 RCV000057915 SCV000089435 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:14998624;PMID:19716085;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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