ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.643C>T (p.Leu215Phe) (rs199472760)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182312 SCV000234615 pathogenic not provided 2011-07-06 criteria provided, single submitter clinical testing 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).
Ambry Genetics RCV000617516 SCV000737827 likely pathogenic Cardiovascular phenotype 2016-11-21 criteria provided, single submitter clinical testing 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; Hedley PL et al. Cardiovasc J Afr. 2013;24:231-7). In functional in vitro analyses, this variant has been suggested 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845338 SCV000987384 likely pathogenic Long QT syndrome criteria provided, single submitter clinical testing
Invitae RCV000845338 SCV001588722 pathogenic Long QT syndrome 2020-01-31 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 342 of the KCNQ1 protein (p.Leu342Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of long QT syndrome (PMID: 26675252, 24217263, 9386136, Invitae). ClinVar contains an entry for this variant (Variation ID: 52932). This variant has been reported to affect KCNQ1 protein function (PMID: 9312006). For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057529 SCV000089048 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: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.

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