ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1216C>T (p.Arg406Trp) (rs199472793)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Medical Genetics and Genomics,Sir Ganga Ram Hospital RCV000234802 SCV000240228 pathogenic Long QT syndrome 1 2014-01-01 criteria provided, single submitter research
Invitae RCV000456908 SCV000543304 uncertain significance Long QT syndrome 2016-06-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 533 of the KCNQ1 protein (p.Arg533Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (rs199472793, ExAC no frequency). This variant has been reported in the homozygous state in two siblings with, a QT interval within the normal range, normal hearing, and a history of syncope. Five heterozygous relatives were asymptomatic (PMID: 10728423). This variant was also reported in the heterozygous state in several individuals referred for long QT syndrome testing whose phenotype could not be confirmed (PMID: 19716085, 20851114). ClinVar contains an entry for this variant (Variation ID: 67041). Experimental studies have not demonstrated a significant difference in KCNQ1 activity compared to wildtype channels, but there is a small positive voltage shift of the channel activation when it is co-expressed with IsK (PMID: 10728423, 24190995). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057603 SCV000089122 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:10728423;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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