ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1847A>G (p.Tyr616Cys) (rs199472946)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000157265 SCV000206995 likely pathogenic Long QT syndrome 2015-01-26 criteria provided, single submitter clinical testing
GeneDx RCV000182032 SCV000234335 pathogenic not provided 2016-07-12 criteria provided, single submitter clinical testing The Tyr616Cys mutation in the KCNH2 gene has been reported previously in one individual referred for LQTS testing, and this mutation was absent from 2,600 alleles from control individuals of various ethnic backgrounds. In addition, the Tyr616Cys mutation was not detected in up to 600 alleles from control individuals of Caucasian and African American ancestry tested at GeneDx, indicating it is not a common benign variant in these populations. Located in the intramembrane pore-forming H5 domain of KCNH2, Tyr616Cys represents a semi-conservative amino acid change of a neutral, polar Tyrosine residue with a neutral, polar Cysteine that can affect disulfide bonds and protein structure. In addition, mutations at surrounding codons (Leu615Phe, Leu615Val, Ala614Val, Thr613Met) have also been reported in association with LQTS, further supporting the functional importance of this region of the protein (6). In summary, the presence of Tyr616Cys in the KCNH2 gene is consistent with a diagnosis of LQTS. The variant is found in LQT panel(s).
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058013 SCV000089533 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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