ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.520C>T (p.Arg174Cys)
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.520C>T (p.Arg174Cys)
Variation ID: 53058 Accession: VCV000053058.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2570670 (GRCh38) [ NCBI UCSC ] 11: 2591900 (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 Feb 20, 2024 Oct 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.520C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Arg174Cys missense NM_001406836.1:c.520C>T NP_001393765.1:p.Arg174Cys missense NM_001406837.1:c.250C>T NP_001393766.1:p.Arg84Cys missense NM_181798.2:c.139C>T NP_861463.1:p.Arg47Cys missense NR_040711.2:n.413C>T NC_000011.10:g.2570670C>T NC_000011.9:g.2591900C>T NG_008935.1:g.130680C>T LRG_287:g.130680C>T LRG_287t1:c.520C>T LRG_287p1:p.Arg174Cys LRG_287t2:c.139C>T LRG_287p2:p.Arg47Cys P51787:p.Arg174Cys - Protein change
- R174C, R47C, R84C
- Other names
- p.R174C:CGC>TGC
- Canonical SPDI
- NC_000011.10:2570669: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) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 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
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 |
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
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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Oct 14, 2023 | RCV000046072.20 | |
not provided (1) |
no classification provided
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- | RCV000057689.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 14, 2021 | RCV000182078.18 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2023 | RCV000587627.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 4, 2018 | RCV001841647.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 11, 2021 | RCV002504938.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 28, 2021 | RCV002345338.8 |
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
(Feb 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695990.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The c.520C>T (p.R174C) in KCNQ1 gene is a missense variant that involves a conserved nucleotide and 5/5 in silico tools predict deleterious outcome. … (more)
Variant summary: The c.520C>T (p.R174C) in KCNQ1 gene is a missense variant that involves a conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant is present in the control population dataset of ExAC at a low frequency (0.0008%) which does not exceed the maximum allele frequency for a pathogenic KCNQ1 variant (0.01%). This variant has been reported in the literature in multiple affected individuals presented with elongated QTc interval, including one homozygous pt with severe arrhythmic presentation. Other alterations of the same codon, p.R174H, p.R174L and p.R174P have been reported in pts with LQTS. Functional studies showed p.R174C alters the normal channel activity. In addition, several reputable databases/clinical laboratories classified the variant as Pathogenic. Therefore, this variant was classified as Pathogenic. (less)
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Likely pathogenic
(Nov 04, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001350155.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This missense variant is located in the cytoplasmic linker between transmembrane domains S2 and S3 of the KCNQ1 protein. Computational prediction tools and conservation analyses … (more)
This missense variant is located in the cytoplasmic linker between transmembrane domains S2 and S3 of the KCNQ1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental functional studies have shown that this variant adversely affects KCNQ1 channel function (PMID: 9312006, 19934648, 29449639). This variant has been reported in multiple unrelated individuals affected with long QT syndrome (PMID: 11668638, 23130128, 27251404, 29449639) and in individuals referred for long QT syndrome testing (PMID: 15840476, 19716085). This variant has also been reported in the homozygous and compound heterozygous state in individuals affected with Jervell and Lange-Nielsen syndrome (PMID: 23392653, 29037160). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. (less)
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Pathogenic
(Dec 28, 2021)
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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: SCV002646655.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R174C pathogenic mutation (also known as c.520C>T), located in coding exon 3 of the KCNQ1 gene, results from a C to T substitution at … (more)
The p.R174C pathogenic mutation (also known as c.520C>T), located in coding exon 3 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 520. The arginine at codon 174 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the S2/S3 transmembrane-spanning region. This variant has been reported in long QT syndrome (LQTS) cohorts and LQTS genetic testing cohorts, where some cases had limited details provided (Donger C et al. Circulation. 1997;96(9):2778-81; Splawski I et al. Circulation. 2000;102(10):1178-85; Tester DJ. Heart Rhythm. 2005;2(5):507-17; Couderc JP et al. J Am Heart Assoc. 2012;1:e000570; Miyazaki et al. JACC: Clin Electrophys. 2016;(2)3:266-76; Westphal DS et al. Mol Genet Genomic Med, 2020 09;8:e1300). This variant has also been reported in the homozygous and compound heterozygous states in patients with severe LQTS presentation and Jervell and Lange-Nielsen syndrome (Giudicessi JR et al. Circ Cardiovasc Genet. 2013;6(2):193-200; Uysal F et al. BMC Med Genet. 2017 10;18:114). This variant was also detected in two siblings with LQTS who had additional co-occurring variants in other arrhythmia-related genes; family members heterozygous for p.R174C with QTc values in the normal range were also described (Wu J et al. Sci Rep, 2018 02;8:3129). Functional studies have reported this alteration to disrupt regulation of ion channel activation and lead to impaired ion channel function (Chouabe C et al. EMBO J. 1997;16(17):5472-9; Matavel A et al. Channels (Austin). 2010;4(1):3-11; Huang H et al. Sci Adv, 2018 03;4:eaar2631). Furthermore, other variants affecting this amino acid (p.R174H, p.R174P, and p.R174L) have also been reported in LQTS cohorts (Lupoglazoff JM et al. J. Am Coll Cardiol. 2004;43(5):826-30; Napolitano C et al. JAMA. 2005; 294:2975-80; Aziz PF et al. Circ Arrhythm Electrophysiol. 2011;4:867-73). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
(Nov 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV003839125.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
Comment:
This KCNQ1 variant (rs199472696) is rare (<0.1%) in a large population dataset (gnomAD: 1/249462 total alleles; 0.0004%; no homozygotes) and has been reported in ClinVar5. … (more)
This KCNQ1 variant (rs199472696) is rare (<0.1%) in a large population dataset (gnomAD: 1/249462 total alleles; 0.0004%; no homozygotes) and has been reported in ClinVar5. This variant has been reported in the literature in multiple unrelated individuals affected with long QT syndrome. Alterations of the same codon have also been reported in individuals with LQT1. Experimental studies have shown that this amino acid substitution (p.Arg174Cys) adversely affects KCNQ1 channel function. Bioinformatic analysis predicts that this missense variant would not affect normal exon 3 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.520C>T to be pathogenic. (less)
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Pathogenic
(Oct 14, 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: SCV000074085.11
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 174 of the KCNQ1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 174 of the KCNQ1 protein (p.Arg174Cys). 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: 9386136, 11668638, 15840476, 19716085, 23130128, 23392653). ClinVar contains an entry for this variant (Variation ID: 53058). 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. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 9312006, 19934648). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 02, 2021)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002103233.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
PP3, PM2_supporting, PM3, PS3, PS4_moderate
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Likely pathogenic
(Oct 11, 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: SCV002816459.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 14, 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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GeneDx
Accession: SCV000234381.16
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect … (more)
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published in vitro functional studies demonstrate a damaging effect as the p.(R174C) variant impairs potassium channel regulation and function (Chouabe et al., 1997; Matavel et al., 2010; Wu et al., 2018); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 53058; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 9312006, 23130128, 10973849, 15840476, 9386136, 26986070, 26907222, 29532034, 22581653, 19841300, 19716085, 19934648, 23392653, 27251404, 23728945, 26669661, 19815527, 27761162, 29037160, 29033053, 29449639, 11668638, 31737537, 32383558) (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: SCV004024200.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023 |
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Pathogenic
(Sep 10, 2015)
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no assertion criteria provided
Method: clinical testing
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Long QT syndrome
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000804994.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
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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: SCV000089208.3
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:11668638;PMID:15840476;PMID:19716085;PMID:19934648). 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:11668638;PMID:15840476;PMID:19716085;PMID:19934648). 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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Reclassification of genetic variants in children with long QT syndrome. | Westphal DS | Molecular genetics & genomic medicine | 2020 | PMID: 32383558 |
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 |
Comprehensive analysis of syndromic hearing loss patients in Japan. | Ideura M | Scientific reports | 2019 | PMID: 31427586 |
Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations. | Huang H | Science advances | 2018 | PMID: 29532034 |
A hERG mutation E1039X produced a synergistic lesion on I(Ks) together with KCNQ1-R174C mutation in a LQTS family with three compound mutations. | Wu J | Scientific reports | 2018 | PMID: 29449639 |
"Homozygous, and compound heterozygous mutation in 3 Turkish family with Jervell and Lange-Nielsen syndrome: case reports". | Uysal F | BMC medical genetics | 2017 | PMID: 29037160 |
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 |
Genotype- and mutation site-specific QT adaptation during exercise, recovery, and postural changes in children with long-QT syndrome. | Aziz PF | Circulation. Arrhythmia and electrophysiology | 2011 | PMID: 21956039 |
PKA and PKC partially rescue long QT type 1 phenotype by restoring channel-PIP2 interactions. | Matavel A | Channels (Austin, Tex.) | 2010 | PMID: 19934648 |
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 |
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 |
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. | Tester DJ | Heart rhythm | 2005 | PMID: 15840476 |
Automated mutation screening using dideoxy fingerprinting and capillary array electrophoresis. | Larsen LA | Human mutation | 2001 | PMID: 11668638 |
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. | Splawski I | Circulation | 2000 | PMID: 10973849 |
Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk. | Chouabe C | Cardiovascular research | 2000 | PMID: 10728423 |
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 rs199472696 ...
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.