Submissions for variant NM_172057.2(KCNH2):c.2213A>G (p.Tyr738Cys) (rs199473029)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000455396	SCV000539445	uncertain significance	not specified	2016-07-26	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 LQT proband (PMID 19716085), functional study (PMID 25417810) shows this variant does not impact trafficking
Invitae	RCV000684931	SCV000812394	uncertain significance	Long QT syndrome	2018-06-04	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine with cysteine at codon 1078 of the KCNH2 protein (p.Tyr1078Cys). The tyrosine residue is moderately 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 reported in an individual reffered for LQTS genetic testing, however it is not known if this individual was affected with KCNH2-related conditions (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67483). This variant identified in the KCNH2 gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 19841300, 25348405). However, experimental studies have shown that this missense change does not have an effect on trafficking the KCNH2 protein to the plasma membrane (PMID: 25417810). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust	RCV000058212	SCV000089732	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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