rs199472709
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000218.3(KCNQ1):c.692G>A(p.Arg231His) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R231C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000218.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.692G>A | p.Arg231His | missense_variant | 5/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.692G>A | p.Arg231His | missense_variant | 5/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.311G>A | p.Arg104His | missense_variant | 5/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.431G>A | p.Arg144His | missense_variant | 6/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.478-11414G>A | intron_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460216Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726432
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Apr 06, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 08, 2020 | Identified in several patient with LQTS in published literature (Napolitano et al., 2005; Johnson et al., 2008; Kapplinger et al., 2009; Bartos et al. 2013; Laksman et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a gain of function evidenced by increased channel current and loss of voltage-dependent gating (Bartos et al., 2013); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#53087; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 19716085, 23851063, 24861447, 23350853, 16414944, 18452873, 24721657, 24096004) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 05, 2023 | - - |
Atrial fibrillation, familial, 3 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000053087). Different missense changes at the same codon (p.Arg231Cys, p.Arg231Leu, p.Arg231Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000053086, VCV000280173, VCV000519257). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2013 | - - |
Long QT syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2013 | - - |
Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 231 of the KCNQ1 protein (p.Arg231His). This variant is present in population databases (rs199472709, gnomAD 0.3%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 16414944, 23350853, 24861447). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53087). 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%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 23350853). This variant disrupts the p.Arg231 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15176425, 20850564, 22509038). 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
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 26, 2021 | The p.R231H pathogenic mutation (also known as c.692G>A), located in coding exon 5 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 692. The arginine at codon 231 is replaced by histidine, an amino acid with highly similar properties, and is located within the S4 transmembrane voltage sensor of the potassium channel. This mutation has been reported in individuals with atrial fibrillation and/or prolonged QTc and demonstrated segregation with disease in affected family members in multiple families (Johnson JN et al. Heart Rhythm, 2008 May;5:704-9; Bartos DC et al. J Cardiovasc Electrophysiol, 2013 May;24:562-9; Napolitano C et al. JAMA, 2005 Dec;294:2975-80; Guerrier K et al. Heart Rhythm, 2013 Sep;10:1351-3; Goodyer WR et al. Circ Genom Precis Med, 2019 11;12:e002713). Functional studies demonstrated suppressed PKA regulation, increased KCNQ1 potassium current, and super-trafficking (Bartos DC et al. J Cardiovasc Electrophysiol, 2013 May;24:562-9; Huang H et al. J Biol Chem, 2021 Feb;:100423). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Congenital long QT syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16414944;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