ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1790A>G (p.Tyr597Cys) (rs199472934)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168208 SCV000218873 likely pathogenic Long QT syndrome 2015-11-18 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cystine at codon 597 of the KCNH2 protein (p.Tyr597Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cystine. This variant is not present in population databases (rs199472934, ExAC no frequency). It has been reported in one individual referred for genetic testing for long QT syndrome (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67277). The Tyr597 amino acid is found in the S5-P linker domain of the KCNH2 protein. Experimental studies have shown that this missense change may lead to aberrant disulfide bridge formation (PMID: 12407082) and leads to abnormal protein trafficking (PMID: 25417810). In summary, this is a rare missense change that is predicted to affect protein function and shows segregation with the disease in this family. For these reasons, this variant has been classified as Likely Pathogenic.
GeneDx RCV000414552 SCV000490927 likely pathogenic not provided 2015-11-12 criteria provided, single submitter clinical testing The Y597C likely pathogenic variant in the KCNH2 gene has been reported previously in one individual referred for LQTS genetic testing, and was absent from 2,600 control alleles (Kapplinger et al., 2009). Additionally, Y597C was observed in other unrelated individuals referred for LQTS genetic testing at GeneDx and was classified in ClinVar as a variant of uncertain significance by another clinical laboratory (Landrum et al., 2014). The Y597C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y597C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position that is conserved across species. Furthermore, functional studies show that the Y597C variant results in deficient protein trafficking (Anderson et al., 2014). Therefore, this variant is likely pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057993 SCV000089513 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:19716085). 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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