ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.806G>A (p.Gly269Asp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000218.3(KCNQ1):c.806G>A (p.Gly269Asp)
Variation ID: 3145 Accession: VCV000003145.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2572871 (GRCh38) [ NCBI UCSC ] 11: 2594101 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Apr 20, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.806G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Gly269Asp missense NM_001406836.1:c.806G>A NP_001393765.1:p.Gly269Asp missense NM_001406837.1:c.536G>A NP_001393766.1:p.Gly179Asp missense NM_181798.2:c.425G>A NP_861463.1:p.Gly142Asp missense NR_040711.2:n.699G>A NC_000011.10:g.2572871G>A NC_000011.9:g.2594101G>A NG_008935.1:g.132881G>A LRG_287:g.132881G>A LRG_287t1:c.806G>A LRG_287p1:p.Gly269Asp LRG_287t2:c.425G>A LRG_287p2:p.Gly142Asp P51787:p.Gly269Asp - Protein change
- G269D, G142D, G179D
- Other names
- p.G269D:GGC>GAC
- Canonical SPDI
- NC_000011.10:2572870:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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KCNQ1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
1696 | 2580 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Nov 4, 1997 | RCV000003295.3 | |
Pathogenic (2) |
criteria provided, single submitter
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Jun 30, 2023 | RCV000057766.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 4, 2023 | RCV000046133.13 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 23, 2022 | RCV000182119.13 | |
Pathogenic (1) |
criteria provided, single submitter
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May 2, 2022 | RCV002415391.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV003982822.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Aug 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502635.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(May 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002677566.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Congenital long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847298.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Aug 14, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000884051.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Mar 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000234422.13
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Dec 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000074146.12
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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KCNQ1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004796887.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Nov 04, 1997)
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no assertion criteria provided
Method: literature only
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LONG QT SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023453.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 8 affected members of a family with a severe form of dominantly inherited Romano-Ward syndrome (192500), 5 of whom had sudden deaths, Donger et … (more)
In 8 affected members of a family with a severe form of dominantly inherited Romano-Ward syndrome (192500), 5 of whom had sudden deaths, Donger et al. (1997) identified a gly269-to-asp (G269D) mutation in the KCNQ1 gene. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089285.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
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 … (more)
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. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
Paralogous annotation of disease-causing variants in long QT syndrome genes. | Ware JS | Human mutation | 2012 | PMID: 22581653 |
Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. | Kapplinger JD | Heart rhythm | 2009 | PMID: 19716085 |
Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers. | Berge KE | Scandinavian journal of clinical and laboratory investigation | 2008 | PMID: 18752142 |
Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. | Moss AJ | Circulation | 2007 | PMID: 17470695 |
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. | Tester DJ | Heart rhythm | 2005 | PMID: 15840476 |
Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. | Choi G | Circulation | 2004 | PMID: 15466642 |
Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: multicenter study in Japan. | Shimizu W | Journal of the American College of Cardiology | 2004 | PMID: 15234419 |
Location of mutation in the KCNQ1 and phenotypic presentation of long QT syndrome. | Zareba W | Journal of cardiovascular electrophysiology | 2003 | PMID: 14678125 |
KCNQ1 mutations in patients with a family history of lethal cardiac arrhythmias and sudden death. | Chen S | Clinical genetics | 2003 | PMID: 12702160 |
KCNQ1 gain-of-function mutation in familial atrial fibrillation. | Chen YH | Science (New York, N.Y.) | 2003 | PMID: 12522251 |
Compound heterozygous mutations in KvLQT1 cause Jervell and Lange-Nielsen syndrome. | Wang Z | Molecular genetics and metabolism | 2002 | PMID: 12051962 |
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. | Splawski I | Circulation | 2000 | PMID: 10973849 |
KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. | Donger C | Circulation | 1997 | PMID: 9386136 |
Properties of KvLQT1 K+ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias. | Chouabe C | The EMBO journal | 1997 | PMID: 9312006 |
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Text-mined citations for rs120074194 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.