ClinVar Genomic variation as it relates to human health

Variant summary: KCNQ1 c.613G>A (p.Val205Met) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 276590 control chromosomes. c.613G>A has been reported in the literature in multiple heterozygous individuals of whom several were affected with Long QT syndrome, as well as in four homozygous patients presenting with a more severe cardiac phenotype, and occasionally with symptoms suggestive of Jervell and Lange-Nielsen syndrome (Jackson 2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Arbour 2008). The most pronounced variant effect results in approximately 30%-50% of the normal channel activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate marked alteration of channel activity (Arbour et al., 2008; Eldstrom et al., 2010; Eldstrom et al., 2015); 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: 25637381, 22378279, 18580685, 20421371, 25525159, 23844633, 31447099, 31589614, 31737537, 28264985, 34319147, 27831900, 25444851, Sanatani2022[Article], RidaM2023[Preprint], 26669661, 32009526, 36725074)

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 205 of the KCNQ1 protein (p.Val205Met). This variant is present in population databases (rs151344631, gnomAD 0.008%). This missense change has been observed in individuals with long QT syndrome in members of First Nation communities in British Columbia. It has been observed in the heterozygous and homozygous state in numerous affected individuals, though the severity of the symptoms was variable. In addition, this variant has been observed in unrelated individuals with long QT syndrome (PMID: 18580685, 23844633, 26669661, 27831900). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37255). 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: 18580685, 25444851).

The p.Val205Met variant in KCNQ1 has been reported in 2 individuals with long QT syndrome and segregated with disease in at least 10 affected relatives from bot h families (Arbour 2008). Additionally, four individuals have been reported to b e homozygous for this variant and present with a clinically more severe phenotyp e that did not include hearing loss (Jackson 2014). This variant has also been r eported by other clinical laboratories in ClinVar (variation ID: 3725) and has b een identified in 1/126300 European chromosomes by the Genome Aggregation Databa se (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs151344631). In vitro func tional studies provide evidence that the p.Val205Met variant may impact protein function (Arbour 2008, Eldstrom 2010, Eldstrom 2015). In summary, this variant m eets criteria to be classified as pathogenic for long QT syndrome in an autosoma l dominant manner based upon segregation studies and functional evidence.

The KCNQ1 c.613G>A (p.Val205Met) variant has been reported in the medical literature in individuals affected with long QT syndrome (Arbour L et al., PMID: 18580685; Eldstrom J et al., PMID: 25444851; Jackson H et al., PMID: 23844633; Natarajan P et al., PMID: 27831900). This variant is only observed on 3/281,894 total alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to KCNQ1 protein function. Functional studies suggest that this variant reduces KCNQ1 channel activity, indicating impact to protein function (Arbour L et al., PMID: 18580685; Eldstrom J et al., PMID: 25444851). This variant has been submitted to ClinVar as pathogenic by seven laboratories (variation ID: 37255). Based on available information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

The p.V205M pathogenic mutation (also known as c.613G>A), located in coding exon 4 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 613. The valine at codon 205 is replaced by methionine, an amino acid with highly similar properties. This mutation has been reported in multiple families with long QT syndrome and has been observed with an elevated prevalence in an isolated Northern Canadian population (Arbour L, Genet. Med. 2008 Jul; 10(7):545-50; Kapplinger JD et al. J. Med. Genet., 2017 Mar; Pottinger TD et al. J Am Heart Assoc, 2020 Feb;9:e013808). Additionally, in vitro studies have shown this mutant exhibits altered channel gating kinetics and currents in transfected cells (Arbour L et al. Genet. Med., 2008 Jul;10:545-50; Jackson HA, Clin. Genet. 2014 Jul; 86(1):85-90; Eldstrom J, Heart Rhythm 2015 Feb; 12(2):386-94). Based on the supporting evidence, p.V205M is interpreted as a disease-causing mutation.

KCNQ1: PP1:Strong, PM1, PS3:Moderate, PS4:Moderate, PM2:Supporting, PP3

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:18580685;PMID:20421371;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.