ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.568C>T (p.Arg190Trp)
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.568C>T (p.Arg190Trp)
Variation ID: 53070 Accession: VCV000053070.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2570718 (GRCh38) [ NCBI UCSC ] 11: 2591948 (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 Apr 20, 2024 Nov 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.568C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Arg190Trp missense NM_001406836.1:c.568C>T NP_001393765.1:p.Arg190Trp missense NM_001406837.1:c.298C>T NP_001393766.1:p.Arg100Trp missense NM_181798.2:c.187C>T NP_861463.1:p.Arg63Trp missense NR_040711.2:n.461C>T NC_000011.10:g.2570718C>T NC_000011.9:g.2591948C>T NG_008935.1:g.130728C>T LRG_287:g.130728C>T LRG_287t1:c.568C>T LRG_287p1:p.Arg190Trp LRG_287t2:c.187C>T LRG_287p2:p.Arg63Trp P51787:p.Arg190Trp - Protein change
- R190W, R63W, R100W
- Other names
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- Canonical SPDI
- NC_000011.10:2570717:C:T
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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
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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not provided (1) |
no classification provided
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- | RCV000057705.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2023 | RCV000244400.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 15, 2023 | RCV001380572.7 | |
Pathogenic (3) |
criteria provided, single submitter
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Mar 1, 2022 | RCV001705704.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 1, 2021 | RCV002259313.1 |
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
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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
(Sep 01, 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: SCV000320432.7
First in ClinVar: Oct 02, 2016 Last updated: Oct 28, 2023 |
Comment:
The p.R190W variant (also known as c.568C>T), located in coding exon 3 of the KCNQ1 gene, results from a C to T substitution at nucleotide … (more)
The p.R190W variant (also known as c.568C>T), located in coding exon 3 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 568. The arginine at codon 190 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the S2/S3 transmembrane spanning region of the protein. This alteration has been reported in individuals with long QT syndrome (LQTS) and in a sudden unexplained death victim (Napolitano C et al. JAMA. 2005;294(23):2975-80; Jons C et al. J. Cardiovasc Electrophysiol. 2009;20(8):859-65; Winkel BG et al. J. Cardiovasc Electrophysiol. 2012; 23(10):1092-8; Crotti L et al. J Am Coll Cardiol. 2012; 60(24):2515-24; Cuneo BF et al. Circ Arrhythm Electrophysiol. 2013;6(5):946-51). This variant has also been detected in the homozygous and compound heterozygous (with p.R518* and p.R594Q) states in individuals with autosomal recessive Jervell and Lange-Nielsen syndrome (Winbo A et al. Europace. 2012; 14(12):1799-806; Al-Hassnan ZN et al. Heart Rhythm. 2017;14:1191-1199; Mura M et al. Stem Cell Res. 2018;29:157-161). This alteration showed moderate segregation with disease in a family with a dual phenotype of hypertrophic cardiomyopathy and LQTS and who also had alterations in other cardiac-related genes (Wang L et al. Europace. 2016;18(4):602-9). Another alteration at the same codon, p.R190Q (c.569G>A), have also been reported in association with LQTS (Kapplinger JD, Heart Rhythm 2009;6(9):1297-303). 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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Pathogenic
(Sep 06, 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: SCV001578682.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This missense change has been observed in individuals with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 16414944, 19841298, 22456477, 22539601, 24218437, 25825456). ClinVar … (more)
This missense change has been observed in individuals with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 16414944, 19841298, 22456477, 22539601, 24218437, 25825456). ClinVar contains an entry for this variant (Variation ID: 53070). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg190 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8528244, 10728423, 20660394, 22629021). 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. 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 sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 190 of the KCNQ1 protein (p.Arg190Trp). (less)
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Likely pathogenic
(May 01, 2021)
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criteria provided, single submitter
Method: research
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Long QT syndrome 1
Affected status: unknown
Allele origin:
unknown
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Laan Lab, Human Genetics Research Group, University of Tartu
Accession: SCV002538605.1
First in ClinVar: Jul 02, 2022 Last updated: Jul 02, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Non-obstructive azoospermia (present)
Secondary finding: yes
Method: exome sequencing
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Pathogenic
(Mar 01, 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: SCV000234388.10
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein … (more)
Not observed at a significant frequency in large population cohorts (gnomAD); 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: 20660394, 28438721, 31518351, 27251404, 24218437, 23158531, 23281414, 24552659, 22581653, 20541041, 22882672, 25825456, 26813553, 29677589, 19490272, 31009818, 34319147, 32421437, 23995044, 19841298, 31729605, 35205365, 16414944, 22539601) (less)
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Pathogenic
(Nov 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004825834.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The c.568C>T (p.Arg190Trp) variant in KCNQ1 gene, that encodes for potassium voltage-gated channel subfamily Q member 1, has been identified in multiple unrelated individuals (>30) … (more)
The c.568C>T (p.Arg190Trp) variant in KCNQ1 gene, that encodes for potassium voltage-gated channel subfamily Q member 1, has been identified in multiple unrelated individuals (>30) affected with Long QT syndrome (LQTS) (PMID: 16414944, 19841298, 22456477, 24218437, 25825456, 19490272, 23158531, 28438721, 26813553, 32893267) and in a young individual with sudden unexpected death (PMID: 22882672). This variant has been observed in seven individuals in a family and two individuals in another family including the proband; however, phenotypes of the carrier relatives are not given (PMID: 19841298). This variant has also been observed in heterozygous state in one individual, and compound heterozygous state (with another pathogenic variant p.Arg518*) in one individual with Jervell and Lange-Nielsen syndrome (PMID: 22539601). In-silico computational prediction tools suggest that the p.Arg190Trp variant may have deleterious effect on protein function (REVEL score: 0.895). This variant is found to be rare (1/249344; 0.000004) in the general population database (gnomAD) and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 53070). Other missense variants substituting the same amino acid (p.Arg190Gln, p.Arg190Leu, p.Arg190Pro) are known disease-causing variants reported in multiple individuals with LQTS (PMID: 19716085, 20138589, 31737537, 32383558, 17470695, 32893267) and classified as likely pathogenic/pathogenic by several submitters in ClinVar (ID: 67084, 3117, 237228). Therefore, the c.568C>T (p.Arg190Trp) variant in the KCNQ1 gene is classified as pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001921429.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001930791.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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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: SCV000089224.3
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:16414944;PMID:22539601). 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:16414944;PMID:22539601). 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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Actionable secondary findings following exome sequencing of 836 non-obstructive azoospermia cases and their value in patient management. | Kasak L | Human reproduction (Oxford, England) | 2022 | PMID: 35535697 |
Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 32893267 |
Reclassification of genetic variants in children with long QT syndrome. | Westphal DS | Molecular genetics & genomic medicine | 2020 | PMID: 32383558 |
Targeted molecular genetic testing in young sudden cardiac death victims from Western Denmark. | Larsen MK | International journal of legal medicine | 2020 | PMID: 31729605 |
Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders. | Marschall C | Cardiovascular diagnosis and therapy | 2019 | PMID: 31737537 |
Generation of the human induced pluripotent stem cell (hiPSC) line PSMi005-A from a patient carrying the KCNQ1-R190W mutation. | Mura M | Stem cell research | 2019 | PMID: 31009818 |
Clinical profile and mutation spectrum of long QT syndrome in Saudi Arabia: The impact of consanguinity. | Al-Hassnan ZN | Heart rhythm | 2017 | PMID: 28438721 |
[Relationship between electrocardiographic and genetic mutation (MYH7-H1717Q, MYLK2-K324E and KCNQ1-R190W) phenotype in patients with hypertrophic cardiomyopathy]. | Shao H | Zhonghua xin xue guan bing za zhi | 2016 | PMID: 26813553 |
Dual LQT1 and HCM phenotypes associated with tetrad heterozygous mutations in KCNQ1, MYH7, MYLK2, and TMEM70 genes in a three-generation Chinese family. | Wang L | Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | 2016 | PMID: 25825456 |
In utero diagnosis of long QT syndrome by magnetocardiography. | Cuneo BF | Circulation | 2013 | PMID: 24218437 |
Vagal reflexes following an exercise stress test: a simple clinical tool for gene-specific risk stratification in the long QT syndrome. | Crotti L | Journal of the American College of Cardiology | 2012 | PMID: 23158531 |
The prevalence of mutations in KCNQ1, KCNH2, and SCN5A in an unselected national cohort of young sudden unexplained death cases. | Winkel BG | Journal of cardiovascular electrophysiology | 2012 | PMID: 22882672 |
Genotype-phenotype analysis of three Chinese families with Jervell and Lange-Nielsen syndrome. | Gao Y | Journal of cardiovascular disease research | 2012 | PMID: 22629021 |
Prevalence, mutation spectrum, and cardiac phenotype of the Jervell and Lange-Nielsen syndrome in Sweden. | Winbo A | Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | 2012 | PMID: 22539601 |
Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to β-blocker therapy in type 1 long-QT syndrome. | Barsheshet A | Circulation | 2012 | PMID: 22456477 |
Patient-specific induced pluripotent stem-cell models for long-QT syndrome. | Moretti A | The New England journal of medicine | 2010 | PMID: 20660394 |
A new homozygous mutation of the KCNQ1 gene associated with both Romano-Ward and incomplete Jervell Lange-Nielsen syndromes in two sisters. | Kanovsky J | Heart rhythm | 2010 | PMID: 20138589 |
Prevalence of the congenital long-QT syndrome. | Schwartz PJ | Circulation | 2009 | PMID: 19841298 |
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 |
Mutations in conserved amino acids in the KCNQ1 channel and risk of cardiac events in type-1 long-QT syndrome. | Jons C | Journal of cardiovascular electrophysiology | 2009 | PMID: 19490272 |
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 |
Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. | Napolitano C | JAMA | 2005 | PMID: 16414944 |
Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk. | Chouabe C | Cardiovascular research | 2000 | PMID: 10728423 |
Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. | Wang Q | Nature genetics | 1996 | PMID: 8528244 |
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Text-mined citations for rs199473662 ...
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.