rs199472794
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000218.3(KCNQ1):c.1616G>A(p.Arg539Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R539W) has been classified as Pathogenic.
Frequency
Consequence
NM_000218.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.1616G>A | p.Arg539Gln | missense_variant | Exon 13 of 16 | 1 | NM_000218.3 | ENSP00000155840.2 | ||
KCNQ1 | ENST00000335475.6 | c.1235G>A | p.Arg412Gln | missense_variant | Exon 13 of 16 | 1 | ENSP00000334497.5 | |||
KCNQ1 | ENST00000496887.7 | c.1259G>A | p.Arg420Gln | missense_variant | Exon 13 of 16 | 5 | ENSP00000434560.2 | |||
KCNQ1 | ENST00000646564.2 | c.1076G>A | p.Arg359Gln | missense_variant | Exon 8 of 11 | ENSP00000495806.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1416252Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 699848
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Long QT syndrome 1 Pathogenic:1
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". -
not provided Pathogenic:1
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) -
Long QT syndrome Pathogenic:1
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). 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: 19716085; Invitae). ClinVar contains an entry for this variant (Variation ID: 67042). 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 with a positive predictive value of 95%. 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. For these reasons, this variant has been classified as Pathogenic. -
Cardiovascular phenotype Pathogenic:1
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. -
Cardiac arrhythmia Pathogenic:1
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. -
Congenital long QT syndrome Other:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at