ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.1096C>T (p.Arg366Trp)
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.1096C>T (p.Arg366Trp)
Variation ID: 52955 Accession: VCV000052955.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2585275 (GRCh38) [ NCBI UCSC ] 11: 2606505 (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 Dec 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.1096C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Arg366Trp missense NM_001406837.1:c.826C>T NP_001393766.1:p.Arg276Trp missense NM_181798.2:c.715C>T NP_861463.1:p.Arg239Trp missense NR_040711.2:n.989C>T NC_000011.10:g.2585275C>T NC_000011.9:g.2606505C>T NG_008935.1:g.145285C>T LRG_287:g.145285C>T LRG_287t1:c.1096C>T LRG_287p1:p.Arg366Trp LRG_287t2:c.715C>T LRG_287p2:p.Arg239Trp P51787:p.Arg366Trp - Protein change
- R366W, R239W, R276W
- Other names
- p.R366W:CGG>TGG
- Canonical SPDI
- NC_000011.10:2585274: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.
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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 |
1703 | 2599 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Dec 23, 2023 | RCV000045959.14 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Jul 24, 2017 | RCV000057551.7 | |
Pathogenic (3) |
criteria provided, single submitter
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Jan 10, 2022 | RCV000182173.10 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Oct 12, 2023 | RCV000496023.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 29, 2021 | RCV000617196.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Feb 10, 2015)
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criteria provided, single submitter
Method: research
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Long QT syndrome 1
Affected status: unknown
Allele origin:
unknown,
maternal
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000584099.1 First in ClinVar: Jul 30, 2017 Last updated: Jul 30, 2017 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
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Likely pathogenic
(Jul 24, 2017)
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criteria provided, single submitter
Method: clinical testing
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Congenital long QT syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731642.1
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
Comment:
The p.Arg366Trp variant in KCNQ1 has been reported in >12 individuals with long QT syndrome (Splawski 1998, Choi 2004, Kapplinger 2009, Kapa 2009, Giudicessi 20 … (more)
The p.Arg366Trp variant in KCNQ1 has been reported in >12 individuals with long QT syndrome (Splawski 1998, Choi 2004, Kapplinger 2009, Kapa 2009, Giudicessi 20 12, and Torekov 2014) and has also been reported by other clinical laboratories in ClinVar (Variation ID 52955). This variant was absent from large population s tudies. In vitro functional studies provide some evidence that the p.Arg366Trp v ariant may impact protein function (Shamgar 2006). Computational prediction tool s and conservation analysis suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinic al significance, the p.Arg366Trp variant meets criteria to be likely pathogenic for autosomal dominant long QT syndrome. ACMG/AMP Criteria applied: PM2, PS4_Mo derate, PS3_Supporting, PP3. (less)
Number of individuals with the variant: 2
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Pathogenic
(Jan 10, 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: SCV000234476.15
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Functional studies in cultured mammalian cells and/or Xenopus oocytes demonstrate that R366W impairs calmodulin binding … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Functional studies in cultured mammalian cells and/or Xenopus oocytes demonstrate that R366W impairs calmodulin binding and disrupts channel expression and function (Shamgar et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID#52955; ClinVar); This variant is associated with the following publications: (PMID: 24357532, 26063740, 27231019, 9693036, 22949429, 16556865, 25525159, 15466642, 19716085, 10220146, 14678125, 12388934, 24606995, 26669661, 31737537, 31447099, 29790872, 29740400, 30508507, 34135346, 34691145, 29497013) (less)
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Pathogenic
(Dec 23, 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: SCV000073972.13
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 366 of the KCNQ1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 366 of the KCNQ1 protein (p.Arg366Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 9693036, 15466642, 19716085, 19841300, 22949429, 24357532). ClinVar contains an entry for this variant (Variation ID: 52955). 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: 16556865). This variant disrupts the p.Arg366 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9024139, 10973849, 16556865, 19934648). 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 29, 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: SCV000737621.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.R366W pathogenic mutation (also known as c.1096C>T), located in coding exon 8 of the KCNQ1 gene, results from a C to T substitution at … (more)
The p.R366W pathogenic mutation (also known as c.1096C>T), located in coding exon 8 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1096. The arginine at codon 366 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported multiple times in unrelated individuals reported to have long QT syndrome (LQTS) (Splawski I et al. Genomics. 1998;51(1):86-97; Choi G et al. Circulation. 2004;110(15):2119-24; Itoh H et al. Heart Rhythm. 2010;7(10):1411-8; Giudicessi JR. et al. Circ Cardiovasc Genet. 2012;5(5):519-28; Torekov SS et al. Diabetes. 2014;63(4):1315-25). One in vitro study reported this alteration to result in impaired binding to calmodulin, altered ion channel kinetics, and reduced cell surface expression (Shamgar L et al. Circ Res. 2006;98(8):1055-63). In addition, other alterations affecting the same amino acid (p.R366P (c.1097G>C) and p.R366Q (c.1097G>A)) have also been reported in association with LQTS (Splawski I et al. Circulation. 2000;102(10):1178-85). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jan 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
Affected status: yes
Allele origin:
unknown
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Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV001422302.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
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Pathogenic
(Feb 25, 2020)
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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 Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV001433411.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
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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: SCV004024196.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023 |
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Likely pathogenic
(Oct 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations
Accession: SCV004100810.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
We observed a heterozygous c.1096C>T (p.Arg366Trp) genetic variant in the KCNQ1 gene on WES data in a 7-month-old male proband diagnosed with long QT syndrome. … (more)
We observed a heterozygous c.1096C>T (p.Arg366Trp) genetic variant in the KCNQ1 gene on WES data in a 7-month-old male proband diagnosed with long QT syndrome. ClinVar contains an entry for this variant (Variation ID: 52955) observed in patients with the consistent phenotype. This variant is not present in gnomAD database and located in a mutational hot spot and/or critical and well-established functional domain (PM1_strong according to Walsh R. et al. (PMID: 32893267). Multiple computational resources predict deleterious effect of p.Arg366Trp genetic variant. Functional studies in cultured mammalian cells and/or Xenopus oocytes demonstrate that p.Arg366Trp impairs calmodulin binding and disrupts channel expression and function (PMID: 16556865). For these reasons, this variant has been classified as Likely Pathogenic. (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Russian
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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: SCV001926681.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(Feb 19, 2018)
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no assertion criteria provided
Method: clinical testing
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Long QT syndrome 1
Affected status: yes
Allele origin:
germline
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Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV000863813.1
First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018 |
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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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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958223.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 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: SCV000089070.3
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:9693036;PMID:10220146;PMID:11668638;PMID:14678125;PMID:15466642;PMID:15840476;PMID:16937190;PMID:19716085;PMID:19841300;PMID:10090529). 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:9693036;PMID:10220146;PMID:11668638;PMID:14678125;PMID:15466642;PMID:15840476;PMID:16937190;PMID:19716085;PMID:19841300;PMID:10090529). 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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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 |
Genomic sequencing identifies secondary findings in a cohort of parent study participants. | Thompson ML | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29790872 |
Genetic basis of channelopathies and cardiomyopathies in Hong Kong Chinese patients: a 10-year regional laboratory experience. | Mak CM | Hong Kong medical journal = Xianggang yi xue za zhi | 2018 | PMID: 29497013 |
Follow-up of 316 molecularly defined pediatric long-QT syndrome patients: clinical course, treatments, and side effects. | Koponen M | Circulation. Arrhythmia and electrophysiology | 2015 | PMID: 26063740 |
Next-generation sequencing of 34 genes in sudden unexplained death victims in forensics and in patients with channelopathic cardiac diseases. | Hertz CL | International journal of legal medicine | 2015 | PMID: 25467552 |
Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2. | Christiansen M | BMC medical genetics | 2014 | PMID: 24606995 |
Genetic characteristics of children and adolescents with long-QT syndrome diagnosed by school-based electrocardiographic screening programs. | Yoshinaga M | Circulation. Arrhythmia and electrophysiology | 2014 | PMID: 24363352 |
KCNQ1 long QT syndrome patients have hyperinsulinemia and symptomatic hypoglycemia. | Torekov SS | Diabetes | 2014 | PMID: 24357532 |
Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome. | Giudicessi JR | Circulation. Cardiovascular genetics | 2012 | PMID: 22949429 |
Prevalence of HCM and long QT syndrome mutations in young sudden cardiac death-related cases. | Allegue C | International journal of legal medicine | 2011 | PMID: 21499742 |
Long QT syndrome with compound mutations is associated with a more severe phenotype: a Japanese multicenter study. | Itoh H | Heart rhythm | 2010 | PMID: 20541041 |
Analysis of the interactions between the C-terminal cytoplasmic domains of KCNQ1 and KCNE1 channel subunits. | Zheng R | The Biochemical journal | 2010 | PMID: 20196769 |
PKA and PKC partially rescue long QT type 1 phenotype by restoring channel-PIP2 interactions. | Matavel A | Channels (Austin, Tex.) | 2010 | PMID: 19934648 |
Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. | Kapa S | Circulation | 2009 | PMID: 19841300 |
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 |
Classification of the long-QT syndrome based on discriminant analysis of T-wave morphology. | Struijk JJ | Medical & biological engineering & computing | 2006 | PMID: 16937190 |
Calmodulin is essential for cardiac IKS channel gating and assembly: impaired function in long-QT mutations. | Shamgar L | Circulation research | 2006 | PMID: 16556865 |
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 |
Location of mutation in the KCNQ1 and phenotypic presentation of long QT syndrome. | Zareba W | Journal of cardiovascular electrophysiology | 2003 | PMID: 14678125 |
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 |
High-throughput single-strand conformation polymorphism analysis by automated capillary electrophoresis: robust multiplex analysis and pattern-based identification of allelic variants. | Larsen LA | Human mutation | 1999 | PMID: 10220146 |
A single strand conformation polymorphism/heteroduplex (SSCP/HD) method for detection of mutations in 15 exons of the KVLQT1 gene, associated with long QT syndrome. | Larsen LA | Clinica chimica acta; international journal of clinical chemistry | 1999 | PMID: 10090529 |
Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1. | Splawski I | Genomics | 1998 | PMID: 9693036 |
Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome. | Tanaka T | Circulation | 1997 | PMID: 9024139 |
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Text-mined citations for rs199473411 ...
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.