ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.805G>A (p.Gly269Ser)
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.805G>A (p.Gly269Ser)
Variation ID: 3144 Accession: VCV000003144.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2572870 (GRCh38) [ NCBI UCSC ] 11: 2594100 (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 Oct 9, 2016 May 1, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.805G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Gly269Ser missense NM_001406836.1:c.805G>A NP_001393765.1:p.Gly269Ser missense NM_001406837.1:c.535G>A NP_001393766.1:p.Gly179Ser missense NM_181798.2:c.424G>A NP_861463.1:p.Gly142Ser missense NR_040711.2:n.698G>A NC_000011.10:g.2572870G>A NC_000011.9:g.2594100G>A NG_008935.1:g.132880G>A LRG_287:g.132880G>A LRG_287t1:c.805G>A LRG_287p1:p.Gly269Ser LRG_287t2:c.424G>A LRG_287p2:p.Gly142Ser P51787:p.Gly269Ser - Protein change
- G269S, G142S, G179S
- Other names
- p.G269S:GGC>AGC
- Canonical SPDI
- NC_000011.10:2572869: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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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
- | 2663 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (2) |
criteria provided, single submitter
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Aug 1, 2023 | RCV000003294.5 | |
not provided (1) |
no classification provided
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- | RCV000057765.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 22, 2024 | RCV000477568.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 27, 2023 | RCV000182118.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000762834.3 | |
Pathogenic (1) |
criteria provided, single submitter
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May 22, 2019 | RCV001002562.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 25, 2019 | RCV002408447.2 |
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
Help
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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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Beckwith-Wiedemann syndrome
Long QT syndrome 1 Long QT syndrome 1 Jervell and Lange-Nielsen syndrome 1 Atrial fibrillation, familial, 3 Short QT syndrome type 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893193.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(May 22, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001160534.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The c.805G>A; p.Gly269Ser variant (rs120074193, ClinVarID 3144 ) was first reported in a 16-year-old asymptomatic boy, whose cousin passed out in a swimming pool due … (more)
The c.805G>A; p.Gly269Ser variant (rs120074193, ClinVarID 3144 ) was first reported in a 16-year-old asymptomatic boy, whose cousin passed out in a swimming pool due to a triggered cardiac event (Ackerman 1999). This patient's QT was measured at 470 ms. Since then, the p.Gly269Ser variant has been reported in patients with long QT syndrome, including at least four families, where the variant segregated with disease (Wu 2014, Fujii 2017). Additionally, other amino acid substitutions at this codon (p.Gly269Asp, p.Gly269Val) have been reported in individuals with LQTS and are considered pathogenic (Donger 1997, and ClinVar IDs: 3145 & 200899). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 269 is highly conserved in the transmembrane S5 domain, and functional studies demonstrate that the p.Gly269Ser variant causes a reduction in potassium ion current and protein stability (Wu 2014 and Verma 2010). Computational analyses by SIFT and PolyPhen-2 also predict that this variant is deleterious. Overall, this variant is considered to be pathogenic. (less)
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Pathogenic
(Jul 27, 2023)
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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: SCV000234421.13
First in ClinVar: Jul 05, 2015 Last updated: Aug 18, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant may cause abnormal assembly and … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant may cause abnormal assembly and stability of the potassium channel and exert moderate dominant-negative suppression of the potassium channel (Verma et al., 2009; Wu et al., 2014; Wang et al., 2014); 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: 25348405, 20044973, 19808498, 27816319, 22677073, 29740400, 29439887, 15234419, 15176425, 18752142, 19841300, 9312006, 9386136, 10973849, 12051962, 12522251, 17470695, 31328865, 29151524, 25082577, 33087929, 10560595, 34319147, 32470535, 34505893, 24184248) (less)
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Pathogenic
(Aug 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes
Accession: SCV004024212.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023 |
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Pathogenic
(Jan 22, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000543295.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 269 of the KCNQ1 protein (p.Gly269Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 269 of the KCNQ1 protein (p.Gly269Ser). This variant is present in population databases (rs120074193, gnomAD 0.003%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 15176425, 15234419, 18752142, 24184248). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3144). 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: 20044973, 24184248). This variant disrupts the p.Gly269 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9312006, 9386136, 10973849, 12051962, 12522251, 17470695). 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. (less)
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Pathogenic
(Jan 25, 2019)
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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: SCV002675873.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.G269S pathogenic mutation (also known as c.805G>A), located in coding exon 6 of the KCNQ1 gene, results from a G to A substitution at … (more)
The p.G269S pathogenic mutation (also known as c.805G>A), located in coding exon 6 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 805. The glycine at codon 269 is replaced by serine, an amino acid with similar properties. This mutation has been detected in numerous individuals with long QT syndrome (LQTS), some demonstrating symptoms triggered by physical exertion such as swimming; segregation was reported in affected family members from several families (Ackerman MJ et al. Mayo Clin. Proc., 1999 Nov;74:1088-94; Chen S et al. Clin. Genet., 2003 Apr;63:273-82; Shimizu W et al. J. Am. Coll. Cardiol., 2004 Jul;44:117-25; Berge KE et al. Scand. J. Clin. Lab. Invest., 2008;68:362-8). In addition, multiple functional studies suggest this alteration leads to deficient protein function (Murray A et al. J. Med. Genet., 2002 Sep;39:681-5; Wu J et al. J. Am. Coll. Cardiol., 2014 Mar;63:819-27). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Sep 01, 2002)
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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: SCV000023452.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 06, 2017 |
Comment on evidence:
Reardon et al. (1993) reported a family in which the proband had a cardiac arrest at 4 years of age; she and her brother were … (more)
Reardon et al. (1993) reported a family in which the proband had a cardiac arrest at 4 years of age; she and her brother were then found to have a QTc of 490 ms. The parents of the proband were first cousins and there were hearing abnormalities reported in several family members. It was uncertain whether the diagnosis should be Romano-Ward syndrome (192500), which is dominant, or Jervell and Lange-Nielsen syndrome (220400), which is recessive. Murray et al. (2002) identified a gly269-to-ser (G269S) mutation in the KCNQ1 gene in homozygous state in the proband and her brother. Functional studies indicated that the mutation had both recessive and dominant characteristics. (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: SCV000089284.3
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:10560595;PMID:12205113;PMID:12702160;PMID:14678125;PMID:15466642;PMID:15840476;PMID:17905336;PMID:18752142;PMID:19716085;PMID:19808498;PMID:20044973;PMID:15234419;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:10560595;PMID:12205113;PMID:12702160;PMID:14678125;PMID:15466642;PMID:15840476;PMID:17905336;PMID:18752142;PMID:19716085;PMID:19808498;PMID:20044973;PMID:15234419;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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The Role of KCNQ1 Mutations and Maternal Beta Blocker Use During Pregnancy in the Growth of Children With Long QT Syndrome. | Huttunen H | Frontiers in endocrinology | 2018 | PMID: 29740400 |
Contribution of a KCNH2 variant in genotyped long QT syndrome: Romano-Ward syndrome under double mutations and acquired long QT syndrome under heterozygote. | Fujii Y | Journal of cardiology | 2017 | PMID: 27816319 |
Molecular pathogenesis of long QT syndrome type 1. | Wu J | Journal of arrhythmia | 2016 | PMID: 27761162 |
A molecular mechanism for adrenergic-induced long QT syndrome. | Wu J | Journal of the American College of Cardiology | 2014 | PMID: 24184248 |
Cardiac channel molecular autopsy: insights from 173 consecutive cases of autopsy-negative sudden unexplained death referred for postmortem genetic testing. | Tester DJ | Mayo Clinic proceedings | 2012 | PMID: 22677073 |
Structural and functional changes in a synthetic S5 segment of KvLQT1 channel as a result of a conserved amino acid substitution that occurs in LQT1 syndrome of human. | Verma R | Biochimica et biophysica acta | 2010 | PMID: 20044973 |
Biophysical properties of 9 KCNQ1 mutations associated with long-QT syndrome. | Yang T | Circulation. Arrhythmia and electrophysiology | 2009 | PMID: 19808498 |
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 |
Long QT and Brugada syndrome gene mutations in New Zealand. | Chung SK | Heart rhythm | 2007 | PMID: 17905336 |
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 |
Four potassium channel mutations account for 73% of the genetic spectrum underlying long-QT syndrome (LQTS) and provide evidence for a strong founder effect in Finland. | Fodstad H | Annals of medicine | 2004 | PMID: 15176425 |
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 |
Mutation in KCNQ1 that has both recessive and dominant characteristics. | Murray A | Journal of medical genetics | 2002 | PMID: 12205113 |
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 |
Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome. | Ackerman MJ | Mayo Clinic proceedings | 1999 | PMID: 10560595 |
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 |
Consanguinity, cardiac arrest, hearing impairment, and ECG abnormalities: counselling pitfalls in the Romano-Ward syndrome. | Reardon W | Journal of medical genetics | 1993 | PMID: 8487283 |
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Text-mined citations for rs120074193 ...
HelpRecord last updated Sep 29, 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.