Submissions for variant NM_000218.3(KCNQ1):c.716T>C (p.Leu239Pro)

dbSNP: rs199473458

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002371884	SCV002662267	likely pathogenic	Cardiovascular phenotype	2018-09-07	criteria provided, single submitter	clinical testing	The p.L239P variant (also known as c.716T>C), located in coding exon 5 of the KCNQ1 gene, results from a T to C substitution at nucleotide position 716. The leucine at codon 239 is replaced by proline, an amino acid with similar properties. This variant was identified in a cohort of individuals with long QT syndrome; however, specific clinical details were not provided (Napolitano C et al. JAMA, 2005 Dec;294:2975-80). In Xenopus oocytes, this variant reduced current and exhibited an increased rate of deactivation; when expressed with wild type KCNQ1 and also KCNE1, the current was decreased by more than 50% compared to wild type KCNQ1 and KCNE1 (Henrion U et al. Cell. Physiol. Biochem., 2009 Jul;24:11-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005089430	SCV005835795	uncertain significance	Long QT syndrome	2024-05-15	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 239 of the KCNQ1 protein (p.Leu239Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Long QT Syndrome (PMID: 16414944, 34505893). ClinVar contains an entry for this variant (Variation ID: 53089). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 19590188). 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	RCV000057736	SCV000089255	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:16414944;PMID:19590188). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.