ClinVar Genomic variation as it relates to human health

This missense variant replaces arginine with glutamine at codon 539 in the C-terminal cytoplasmic domain of the KCNQ1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in multiple individuals referred for long QT syndrome genetic testing (PMID: 19716085) or affected with long QT syndrome (PMID: 27920829, 28566242). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the the same codon (p.Arg539Trp) is known to cause long QT syndrome (Clinvar variation ID 52998), suggesting that arginine at this position is important for the protein function. Based on available evidence, this variant is classified as Likely Pathogenic.

The KCNQ1 Arg539Gln has been reported previously in a case control study of 2500 patients referred for long QT genetic testing (Kapplinger JD, et al., 2009), as well as a long QT patient (Cardiovascular Biomedical Research Unit Royal Brompton & Harefield NHS Foundation Trust ClinVar: SCV000089124). Interestingly, another rare variant at this position (KCNQ1 Arg539Trp) has been classified as pathogenic; suggesting that an amino acid substitution at this site may not be tolerated. We have identified this KCNQ1 Arg539Gln variant in one long QT case, and the variant was found to segregate to another affected family member. The variant is absent in the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to have a deleterious effect. This variant was discussed at our multidisciplinary pathogenicity meeting and based on rarity in the general population, pathogenic classification of another amino acid substitution at the same position, our familial data, in silico tools supportive of a deleterious effect and because the proband has a typical LQT1 phenotype which is known to be caused by genetic variation in only the KCNQ1 gene, we classify KCNQ1 Arg539Gln as "likely pathogenic".

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg539 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23098067, 23251633, 23631430, 24681627, 25559286). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 67042). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 19716085; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 539 of the KCNQ1 protein (p.Arg539Gln).

The p.R539Q variant (also known as c.1616G>A), located in coding exon 13 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1616. The arginine at codon 539 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in individuals with concerns for long QT syndrome, including individuals with sudden cardiac arrest (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Burns C et al. J Arrhythm, 2016 Dec;32:456-461; Jiménez-Jáimez J et al. Rev Esp Cardiol (Engl Ed), 2017 Oct;70:808-816; Walsh R et al. Genet Med, 2021 Jan;23:47-58; Ambry internal data). Based on internal structural analysis, this alteration disrupts the interaction with PIP2 which stabilizes the channel open state (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well 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.

Reported in one individual with sudden cardiac arrest and a clinical diagnosis of Jervell and Lange-Nielsen syndrome and in individuals referred for LQTS genetic testing at GeneDx and in published literature (PMID: 28566242, 27920829, 19716085); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19716085, 27920829, 28566242, 36243179)

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