ClinVar Genomic variation as it relates to human health

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala344 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9386136, 16922724, 17088455, 17470695, 19490272, 24217263). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 67006). This missense change has been observed in individuals with long QT syndrome (PMID: 15234419, 15840476, 19261104, 21511995, 23098067). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 344 of the KCNQ1 protein (p.Ala344Glu).

The p.A344E variant (also known as c.1031C>A), located in coding exon 7 of the KCNQ1 gene, results from a C to A substitution at nucleotide position 1031. The alanine at codon 344 is replaced by glutamic acid, an amino acid with dissimilar properties, and is located in the S6 region of the KCNQ1 protein. This alteration has been reported in a number of long QT syndrome (LQTS) cohorts (Shimizu W et al. J. Am. Coll. Cardiol. 2004;44:117-25; Tester DJ et al. Heart Rhythm. 2005;2:507-17; Yasuda K et al. Pediatr Int. 2008;50:611-4; Horigome H et al. Circ Arrhythm Electrophysiol. 2011;4:456-64; Stattin EL et al. BMC Cardiovasc Disord. 2012;12:95; Miyazaki A et al. JACC:Clinical Electrophysiology. 2016;2(3):266-76). In one study, an RNA assay indicated that this alteration leads to a splicing defect (Itoh H et al. Eur. J. Hum. Genet. 2016;24:1160-6). Multiple alterations in the same codon (c.1031C>T p.A344V, c.1031C>G p.A344G, c.1032G>C p.A344A, c.1032G>T p.A344A, and c.1032G>T p.A344A) have been associated with LQTS (Donger C et al. Circulation. 1997;96:2778-81; Kanters JK et al. J. Cardiovasc. Electrophysiol.1998;9:620-4; Murray A e tal. Circulation. 1999;100(10):1077-84; Burns C et al. J Arrhythm. 2016;32:456-461). 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.

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Ala344Glu Given small amount of case data and absence of segregation data, we consider this variant of uncertain significance, probably disease causing. The variant has been seen in at least 2 unrelated cases of long QT syndrome with no segregation data. This variant is located in a non-pore region of the gene in exon 7. Shimizu W et al. (2004) reported this variant in one family with long QT syndrome. Specific phenotype data for this family was not given. The study population was 37 unrelated Japanese LQT1 families. Tester D et al. (2005) reported this variant in one family with long QT in their compendium. This cohort is 541 individuals referred to Mayo Clinic's Sudden Death Genomic Clinic (Ackerman) who underwent testing for variants in KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6) between August 1997 and July 2004. No specific phenotype data was given for this family. It should be noted that the authors state that regardless of the clinical diagnostic score for LQTS (“Schwartz score”), a sample was accepted for genetic testing if the referring physician had made a tentative clinical diagnosis of LQTS. The authors note that be considered as a probable pathogenic LQTS causing variant, the nonsynonymous variant must have been absent in all published databases of channel polymorphisms and their previous comprehensive analysis of 1,488 reference alleles. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The arginine at codon 344 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (Ala344Val, which we classify as very likely disease causing) and nearby codons (p.Pro343Arg; p.Pro343Ser; p.Pro343Lys; p.G345Arg; p.G345E). In total the variant has not been seen in ~7,244 published controls and individuals from publicly available population datasets. There is no variation at codon 344 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 2/7/14). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 2/7/14). The variant was not observed in the following published control samples: Tester et al did not report this variant in 744 control individuals Sequencing of individuals from the general population has shown that 8-10% of all individuals have a rare or novel variant in one of the long QT genes included in this test (Kapa et al 2009, Callis et al 2012). Thus when we find a novel variant in a long QT gene it could either be a causative variant or one of the many benign unique variants we all have.

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15234419;PMID:15840476). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.