ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.521G>A (p.Arg174His)
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.521G>A (p.Arg174His)
Variation ID: 53059 Accession: VCV000053059.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2570671 (GRCh38) [ NCBI UCSC ] 11: 2591901 (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 Jun 3, 2016 May 1, 2024 Dec 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.521G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Arg174His missense NM_001406836.1:c.521G>A NP_001393765.1:p.Arg174His missense NM_001406837.1:c.251G>A NP_001393766.1:p.Arg84His missense NM_181798.2:c.140G>A NP_861463.1:p.Arg47His missense NR_040711.2:n.414G>A NC_000011.10:g.2570671G>A NC_000011.9:g.2591901G>A NG_008935.1:g.130681G>A LRG_287:g.130681G>A LRG_287t1:c.521G>A LRG_287p1:p.Arg174His LRG_287t2:c.140G>A LRG_287p2:p.Arg47His P51787:p.Arg174His - Protein change
- R174H, R47H, R84H
- Other names
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- Canonical SPDI
- NC_000011.10:2570670: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 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 |
1702 | 2589 |
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
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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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not provided (1) |
no classification provided
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- | RCV000057690.4 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Jul 31, 2019 | RCV000223741.4 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 8, 2017 | RCV000984322.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 18, 2023 | RCV001386000.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 3, 2021 | RCV002496703.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 16, 2023 | RCV002336182.3 |
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
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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
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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
(Nov 08, 2017)
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criteria provided, single submitter
Method: curation
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Long QT syndrome 1
Affected status: unknown
Allele origin:
germline
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: CSER_ClinSeq
Accession: SCV001132518.1 First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
Secondary finding: yes
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Pathogenic
(Dec 03, 2021)
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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: SCV002796331.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 18, 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: SCV001586070.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 174 of the KCNQ1 protein (p.Arg174His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 174 of the KCNQ1 protein (p.Arg174His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with long QT syndrome (PMID: 10973849, 14998624, 19716085, 23130128; Invitae). ClinVar contains an entry for this variant (Variation ID: 53059). 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: 29532034, 30571187). This variant disrupts the p.Arg174 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9386136, 15840476, 23130128, 23392653). 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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Likely pathogenic
(Nov 16, 2023)
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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: SCV002642027.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R174H variant (also known as c.521G>A), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide … (more)
The p.R174H variant (also known as c.521G>A), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 521. The arginine at codon 174 is replaced by histidine, an amino acid with highly similar properties. This variant has been described in association with long QT syndrome (LQTS) (Splawski I et al. Circulation. 2000;102(10):1178-85; Lupoglazoff JM et al. J. Am. Coll. Cardiol. 2004;43(5):826-30; Shimizu W et al. J. Am. Coll. Cardiol. 2004;44(1):117-25; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). Functional analysis suggests this alteration causes a dominant negative trafficking defect (Vanoye CG et al. Circ Genom Precis Med, 2018 11;11:e002345; Huang H et al. Sci Adv. 2018;4:eaar2631). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Jul 31, 2019)
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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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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV001433431.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
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Pathogenic
(Sep 29, 2017)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome, LQT1 subtype
Affected status: yes
Allele origin:
germline
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Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub
Accession: SCV000845652.2
First in ClinVar: Nov 03, 2018 Last updated: Dec 11, 2022 |
Comment:
This variant has been reported in multiple patients with LQTS (1. Denjoy et al. (1999) Arch Mal Coeur Vaiss. 92(5):557-63; Splawski et al. (2000) Circulation. … (more)
This variant has been reported in multiple patients with LQTS (1. Denjoy et al. (1999) Arch Mal Coeur Vaiss. 92(5):557-63; Splawski et al. (2000) Circulation. 102(10):1178-85; Shimizu et al. (2004) J Am Coll Cardiol. 44(1):117-25; Moss et al. (2007) Circulation. 115(19):2481-9; Kapplinger et al. (2009) Heart Rhythm. 6(9):1297-303; Lupoglazoff et al J Am Coll Cardiol. 2004 Mar 3;43(5):82630; ClinVar variation ID 53059), and has been detected in a single individual in control populations (ExAC database 1/16484 alleles). Other variants at the same amino acid residue have also been reported in association with LQTS: p.Arg174Cys (pubmed: 9386136, 15840476, 19716085, 19934648, 9312006, 11668638); p.Arg174Leu (pubmed: 21956039); p.Arg174Pro (pubmed: 16414944). This variant occurs in the Transmembrane/Linker/Pore region of KCNQ1. Variants found in this region have been shown to have a high probability of pathogenicity (Kapa et al. Circulation. 2009 Nov 3; 120(18): 1752–1760). In silico analysis predicts pathogenicity (SIFT; PolyPhen; Mutation Taster; LRT, FATHMM; MutationAssessor) but these predictions have not been confirmed by published functional studies. The affected amino acid residue is highly conserved across species. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Feb 08, 2012)
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no assertion criteria provided
Method: clinical testing
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Not provided
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280155.1
First in ClinVar: Jun 03, 2016 Last updated: Jun 03, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Arg174His Based on the information reviewed below, we classify it as likely disease causing. This variant has previously been reported multiple times, in ~7 unrelated individuals with LQTS (it is unclear if there is any overlap in individuals reported in the following papers). Splawski et al. (2000) reported it for the first time in a proband with LQTS. Shimizu et al. (2004) described its effects in 1 Japanese family. Lupoglazoff et al. (2004) reported it in a neonate with sinus bradycardia and prolonged QT of 500 msec. Moss et al. (2007) reported it in 2 unrelated families in the U.S. International/Netherlands/Japanese LQTS Registries. Kapplinger et al. (2009) reported it in one individual tested for LQTS at Familion. In 2009, clinicians from Kaiser San Diego and UCSD reported it in an abstract at ASHG as a homozygous mutation in a neonate with Jervell and Lange-Nielsen syndrome, whose family members (maternal and paternal) had LQTS. There is no known published segregation data. We do have segregation data within a family at our center, however, and the variant tracks with disease. Other variants at this same amino acid residue have also been reported in association with LQTS according to HGMD: p.Arg174Cys, p.Arg174Leu, p.Arg174Pro. This is a conservative amino acid change, resulting in the replacement of a positively charged arginine with a positively charged histidine, but the side chains are very different in shape. According to cardiodb.org, Arg174 is entirely conserved across 32 paralogue channel proteins. Variation at nearby residues (+10 amino acids) has been associated with LQTS, which supports the functional importance of this region of the protein: p.Gly168Arg, p.Thr169Arg, Glu170Gly, p.Val172Met, p.Val173Asp, p.Ala178Pro, p.Ala178Thr, p.Gly179Ser, p.Lys183Arg, p.Lys183Met, p.Tyr184His, p.Tyr184Ser (HGMD professional version as of January 17, 2014). Arg174 is in a transmembrane spanning region of KCNQ1, and such variants have been shown to have a higher likelihood of being deleterious than variants in other regions of the protein (Kapa et al. 2009). In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 1.0 In total the variant has not been seen in over 7500 published controls and individuals from publicly available population datasets. Kapplinger et al. (2009) did not observe it in 1300 ethnically diverse controls: 47% Caucasian, 26% African-American, 11% Hispanic, 10% Asian, 6% unknown/other. Splawski et al. (200) did not find it in 200 controls. There is no variation at this residue listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also no variation at this residue listed in 1000 Genomes (http://browser.1000genomes.org/index.htm) as of November 6, 2014. (less)
Number of individuals with the variant: 8
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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: SCV000089209.3
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:10367071;PMID:10973849;PMID:14998624;PMID:19716085;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:10367071;PMID:10973849;PMID:14998624;PMID:19716085;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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Mutation location and IKs regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region. | Schwartz PJ | European heart journal | 2021 | PMID: 34505893 |
High-Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance. | Vanoye CG | Circulation. Genomic and precision medicine | 2018 | PMID: 30571187 |
Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations. | Huang H | Science advances | 2018 | PMID: 29532034 |
Semiconductor Whole Exome Sequencing for the Identification of Genetic Variants in Colombian Patients Clinically Diagnosed with Long QT Syndrome. | Burgos M | Molecular diagnosis & therapy | 2016 | PMID: 27251404 |
Prevalence and potential genetic determinants of sensorineural deafness in KCNQ1 homozygosity and compound heterozygosity. | Giudicessi JR | Circulation. Cardiovascular genetics | 2013 | PMID: 23392653 |
Genotype- and Sex-Specific QT-RR Relationship in the Type-1 Long-QT Syndrome. | Couderc JP | Journal of the American Heart Association | 2012 | PMID: 23130128 |
A new approach to long QT syndrome mutation detection by Sequenom MassARRAY system. | Allegue C | Electrophoresis | 2010 | PMID: 20486126 |
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 |
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 |
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 |
Long QT syndrome in neonates: conduction disorders associated with HERG mutations and sinus bradycardia with KCNQ1 mutations. | Lupoglazoff JM | Journal of the American College of Cardiology | 2004 | PMID: 14998624 |
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. | Splawski I | Circulation | 2000 | PMID: 10973849 |
[Congenital long QT syndrome. The value of genetics in prognostic evaluation]. | Denjoy I | Archives des maladies du coeur et des vaisseaux | 1999 | PMID: 10367071 |
KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. | Donger C | Circulation | 1997 | PMID: 9386136 |
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Text-mined citations for rs199472697 ...
HelpRecord last updated May 01, 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.