rs120074194
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000218.3(KCNQ1):c.806G>A(p.Gly269Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. G269S) 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.806G>A | p.Gly269Asp | missense_variant | 6/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.806G>A | p.Gly269Asp | missense_variant | 6/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.425G>A | p.Gly142Asp | missense_variant | 6/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.545G>A | p.Gly182Asp | missense_variant | 7/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.478-10564G>A | intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152250Hom.: 0 Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152250Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74388
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 14, 2017 | The p.Gly269Asp variant (rs120074194) has been reported to segregate with disease in two unrelated families (Donger 1997 and Wang 2002), and was also identified in an individual with a history of near-drowning and a high clinical probability of having long QT syndrome (Choi 2004). The p.Gly269Asp variant was also identified in four out of 2,500 patients (0.16%) suspected of having long-QT syndrome (Kapplinger 2009), but is absent from general population databases such as 1000 Genomes, the Exome Variant Server (ESV), and the Genome Aggregation Database (gnomAD) browser. Functional studies demonstrate that the KCNQ1 p.Gly269Asp substitution eliminates activity of potassium channels (Chen 2003 and Chouabe 1997). Furthermore, another variant at this position (p.Gly269Ser) has been identified in individuals with long QT syndrome (Ackerman 1999, Choi 2004, Kapplinger 2009, Shimizu 2004, and Wu 2014). Based on the available evidence, the p.Gly269Asp variant is considered pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 23, 2022 | Reported in multiple individuals in association with LQTS (Donger et al., 1997; Splawski et al., 2000; Moss et al., 2007; Kapplinger et al., 2009); 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 this variant results in a loss of function of the ion channel (Chouabe et al., 1997; Chen et al., 2003); This variant is associated with the following publications: (PMID: 23130128, 21185501, 19815527, 27761162, 10973849, 14678125, 15466642, 17470695, 12205113, 22629021, 23139254, 25649125, 9312006, 19716085, 15840476, 22581653, 31980526, 34319147, 12051962, 12522251, 9386136) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Aug 05, 2021 | - - |
Congenital long QT syndrome Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 30, 2023 | The p.Gly269Asp variant in KCNQ1 has been reported in the heterozygous state in at least 36 individuals with long QT syndrome (LQTS) and in the compound heterozygous state in 1 individual with Jervell and Lange-Nielsen syndrome (JNLS). This variant segregated with LQTS in 7 relatives from 2 families (Donger 1997 PMID: 9386136, Wang 2002 PMID: 12051962, Moss 2007 PMID: 17470695). This variant has also been reported by other clinical laboratories in Clinvar (Variation ID 3145) and was identified in 0.002% (1/41470) African/African American and in 0.001% (1/68042) European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). In vitro functional studies provide some evidence that this variant results in a non-functional potassium channel (Chouabe 1997 PMID: 9312006, Chen 2003 PMID: 12522251) and computational prediction tools and conservation analyses suggest that this variant impacts the protein. At least 1 additional variant involving this codon (p.Gly269Ser) has been identified in individuals with LQTS and is classified as pathogenic by several clinical laboratories in ClinVar (Variation ID: 3144). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant LQTS. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM5, PP3, PS3_Supporting, PM2_supporting. - |
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:9386136;PMID:10973849;PMID:12051962;PMID:14678125;PMID:15466642;PMID:15840476;PMID:19716085;PMID:17470695). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Long QT syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 04, 1997 | - - |
KCNQ1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 01, 2024 | The KCNQ1 c.806G>A variant is predicted to result in the amino acid substitution p.Gly269Asp. This variant is also known as p.Gly142Asp in the literature. This variant was reported in numerous individuals with long QT syndrome and sudden cardiac death (Donger et al. 1997. PubMed ID: 9386136; online appendix, Goldenberg et al. 2011. PubMed ID: 21185501; eTable 3, Guo et al. 2021. PubMed ID: 34076677; Table SXIII, Choi et al. 2021. PubMed ID: 34319147; Table S1, Schwartz et al. 2021. PubMed ID: 34505893). Functional studies showed that this variant results in a loss-of-function potassium channel (Chouabe et al. 1997. PubMed ID: 9312006; Chen et al. 2003. PubMed ID: 12522251). This variant has not been reported in a large population database, indicating this variant is rare. Different nucleotide substitutions affecting the same amino acid (p.Gly269Ser, p.Gly269Arg) have been reported to be causative for long QT syndrome (Human Gene Mutation Database). Taken together, the c.806G>A (p.Gly269Asp) variant is interpreted as pathogenic. - |
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 269 of the KCNQ1 protein (p.Gly269Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 9386136, 10973849, 12051962, 17470695). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3145). 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: 9312006, 12522251). For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 02, 2022 | The p.G269D pathogenic mutation (also known as c.806G>A), located in coding exon 6 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 806. The glycine at codon 269 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in a number of individuals with long QT syndrome (LQTS) and was shown to segregate with the disease in a few families (Donger C et al. Circulation. 1997;96:2778-81; Splawski I et al. Circulation. 2000;102:1178-85; Wang Z et al. Mol. Genet. Metab. 2002;75:308-16; Moss AJ et al. Circulation. 2007;115:2481-9; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303). In vitro studies suggested that this alteration would affect channel activity (Chouabe C et al. EMBO J. 1997;16:5472-9; Chen YH et al. Science. 2003;299:251-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, another alteration at the same amino acid position, G269S, has also been reported in association with LQTS and to segregate with the disease (Shimizu W et al. J. Am. Coll. Cardiol. 2004;44:117-25; Chen S et al. Clin. Genet. 2003;63:273-82; Berge KE et al. Scand. J. Clin. Lab. Invest. 2008;68:362-8). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at