ClinVar Genomic variation as it relates to human health

This missense change is denoted Leu342Phe (aka L342F) at the protein level and c.1024 C>T at the cDNA level. The Leu342Phe mutation in the KCNQ1 gene has been published previously in association with LQTS (Donger C et al., 1997, Berge K et al.,2008). Donger et al. (1997) first reported Leu342Phe in five individuals in one family, one of whom was considered symptomatic by having the first episode of syncope before the age of 10. The same study did not detect Leu342Phe in 100 controls (Donger C et al., 1997). Leu342Phe, located in the S6 region of the protein, was subsequently described in three members of one family with LQTS (Berge et al, 2008). Mutations in neighboring residues (Ala341Glu, Ala341Gly, Ala341Val, Pro343Arg, Pro343Leu, Pro343Ser) have also been reported in association with LQTS, further supporting the functional importance of this region of the protein. Furthermore, Leu342Phe was not observed in up to 400 control alleles of Caucasian ethnic background tested at GeneDx, indicating it is not a common benign polymorphism in this population. The variant is found in LQT panel(s).

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 342 of the KCNQ1 protein (p.Leu342Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 9386136, 24217263, 26675252; Invitae). ClinVar contains an entry for this variant (Variation ID: 52932). 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. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 9312006). For these reasons, this variant has been classified as Pathogenic.

The p.L342F variant (also known as c.1024C>T), located in coding exon 7 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1024. The leucine at codon 342 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been reported in several long QT syndrome (LQTS) cohorts (Donger C et al. Circulation. 1997;96:2778-81; Berge KE et al. Scand J Clin Lab Invest. 2008;68:362-8; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Stattin EL et al. BMC Cardiovasc Disord. 2012;12:95; Haugaa KH et al. Heart Rhythm, 2013 Dec;10:1877-83; Hedley PL et al. Cardiovasc J Afr. 2013;24:231-7; Izumi G et al. Pediatr Cardiol, 2016 Jun;37:962-70). In functional in vitro analyses, this variant has been shown to decrease potassium channel current density (Chouabe C et al. EMBO J. 1997;16:5472-9). 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.

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:9386136;PMID:18752142;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.