rs199472814
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000218.3(KCNQ1):c.1772G>A(p.Arg591His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,352 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. R591C) has been classified as Likely 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.1772G>A | p.Arg591His | missense_variant | 15/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.1772G>A | p.Arg591His | missense_variant | 15/16 | 1 | NM_000218.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461352Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727014
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 03, 2022 | Reported in multiple individuals in association with LQTS (Neyroud et al., 1999; Inoue et al., 2003; Shimizu et al., 2004; Grunnet et al., 2005; Tester et al., 2005; Moss et al,. 2007; Yasuda et al., 2008; Kapa et al., 2009; Kapplinger et al., 2009; Andrsova et al., 2012; Medlock et al., 2012; Stattin et al., 2012; Cuneo et al., 2013; Robinson et al., 2015; Itoh et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as R591H causes a reduction in potassium ion current due to a reduction in the number of functional voltage-gated potassium channels in the cell membrane (Kanki et al., 2004; Grunnet et al., 2005; Xu et al., 2009); Reported in ClinVar as pathogenic (ClinVar Variant ID# 53017; ClinVar); This variant is associated with the following publications: (PMID: 17470695, 15840476, 17329207, 22949429, 19716085, 19261104, 16253915, 12388934, 18174212, 19825999, 24713462, 19693805, 15140888, 26669661, 23995044, 10024302, 19841300, 15234419, 25916402, 23098067, 22727609, 12808265, 22885918, 17329209, 31395126, 32048431, 31737537) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | KCNQ1: PM1:Strong, PM2, PM5, PS4:Moderate, PP1, PS3:Supporting - |
Long QT syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 05, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 591 of the KCNQ1 protein (p.Arg591His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 10024302, 15234419, 16253915, 19261104, 21482651, 22727609, 22949429). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53017). 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: 16253915, 20662986). This variant disrupts the p.Arg591 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (PMID: 22429796, 22949429, 23158531), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Dept of Medical Biology, Uskudar University | Jan 08, 2024 | Criteria: PS3_Moderate, PS4_Strong, PM1, PM2, PP3 - |
Long QT syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues | Nov 14, 2017 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 20, 2021 | The p.R591H pathogenic mutation (also known as c.1772G>A), located in coding exon 15 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1772. The arginine at codon 591 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in multiple individuals with long QT syndrome (LQTS) and has also been reported in affected relatives (Neyroud N et al. Circ Res, 1999 Feb;84:290-7; Tester DJ et al. Heart Rhythm, 2006 Jul;3:815-21; Robinson JA et al. Congenit Heart Dis Apr;10:354-61; Grunnet M et al. Heart Rhythm, 2005 Nov;2:1238-49; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). Functional studies have demonstrated defective protein trafficking and a significant reduction in potassium channel current (Grunnet M et al. Heart Rhythm, 2005 Nov;2:1238-49; Horr S et al. J Cardiovasc Electrophysiol, 2011 Feb;22:193-200; David JP et al. Traffic, 2013 Apr;14:399-411). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. 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:10024302;PMID:15840476;PMID:16253915;PMID:16818214;PMID:17329209;PMID:19716085;PMID:19841300;PMID:15234419;PMID:17470695;PMID:17329207;PMID:9386136). 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