ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.724G>A (p.Asp242Asn)
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.724G>A (p.Asp242Asn)
Variation ID: 53090 Accession: VCV000053090.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2572053 (GRCh38) [ NCBI UCSC ] 11: 2593283 (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 May 29, 2016 May 1, 2024 Oct 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.724G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Asp242Asn missense NM_001406836.1:c.724G>A NP_001393765.1:p.Asp242Asn missense NM_001406837.1:c.454G>A NP_001393766.1:p.Asp152Asn missense NM_181798.2:c.343G>A NP_861463.1:p.Asp115Asn missense NR_040711.2:n.617G>A NC_000011.10:g.2572053G>A NC_000011.9:g.2593283G>A NG_008935.1:g.132063G>A LRG_287:g.132063G>A LRG_287t1:c.724G>A LRG_287p1:p.Asp242Asn LRG_287t2:c.343G>A LRG_287p2:p.Asp115Asn P51787:p.Asp242Asn - Protein change
- D242N, D115N, D152N
- Other names
- p.D242N:GAC>AAC
- Canonical SPDI
- NC_000011.10:2572052: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
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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Oct 23, 2023 | RCV000046110.9 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Apr 20, 2020 | RCV000057738.5 | |
Pathogenic (2) |
criteria provided, single submitter
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Jun 1, 2023 | RCV000182103.9 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jul 14, 2017 | RCV000656159.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 9, 2022 | RCV002371885.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 1, 2023 | RCV003319312.1 |
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
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 09, 2022)
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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: SCV002671453.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.D242N pathogenic mutation (also known as c.724G>A), located in coding exon 5 of the KCNQ1 gene, results from a G to A substitution at … (more)
The p.D242N pathogenic mutation (also known as c.724G>A), located in coding exon 5 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 724. The aspartic acid at codon 242 is replaced by asparagine, an amino acid with highly similar properties. This mutation has been reported in several patients with long QT syndrome (LQTS), suspected LQTS, or in LQTS cohorts, and has been reported to segregate with disease in families; however, details were limited in some cases (Itoh T et al. Hum. Genet., 1998 Sep;103:290-4; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Moss AJ et al. Circulation, 2007 May;115:2481-9; Jons C et al. J. Cardiovasc. Electrophysiol., 2009 Aug;20:859-65; Izumi G et al. Pediatr Cardiol, 2016 Jun;37:962-70; Moreno C et al. J. Mol. Cell. Cardiol., 2017 09;110:61-69). In addition, in vitro assays indicate that this variant alters channel kinetics (Mousavi Nik A et al. Front Cell Neurosci, 2015 Feb;9:32; Moreno C et al. J. Mol. Cell. Cardiol., 2017 09;110:61-69). This amino acid position is located in the S4 transmembrane voltage sensor helix, and this alteration results in the loss of a negatively charged residue that is well conserved in available vertebrate species. 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)
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Pathogenic
(Jun 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000234406.14
First in ClinVar: Jul 05, 2015 Last updated: Jun 10, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that channels with the D242N variant have reduced current and slowed … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that channels with the D242N variant have reduced current and slowed activation kinetics compared to the wild type channels (Mousavi Nik et al., 2015; Moreno et al., 2017); 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: 17470695, 29167462, 25525159, 27761162, 19490272, 19716085, 15840476, 19862833, 26370830, 27041096, 9799083, 22456477, 28739325, 10973849, 31737537, 34505893, 12388934, 23631430, 25705178) (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: SCV004024162.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023 |
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Pathogenic
(Oct 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: SCV000074123.9
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 242 of the KCNQ1 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 242 of the KCNQ1 protein (p.Asp242Asn). This variant is present in population databases (rs199472712, gnomAD 0.0009%). This missense change has been observed in individuals with long QT syndrome (PMID: 9799083, 17470695, 28739325). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53090). 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: 25705178, 28739325, 29167462). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely Pathogenic
(Apr 20, 2020)
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criteria provided, single submitter
Method: clinical testing
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Congenital long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847826.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Asp242Asn variant in KCNQ1 has been reported in at least 4 individuals with long QT syndrome (LQTS; Itoh 1998 PMID: 9799083, Moss 2007 PMID:17470695, … (more)
The p.Asp242Asn variant in KCNQ1 has been reported in at least 4 individuals with long QT syndrome (LQTS; Itoh 1998 PMID: 9799083, Moss 2007 PMID:17470695, Jons 2009 PMID: 19490272), and in at least 6 individuals with suspected LQTS (Tester 2005 PMID: 15840476, Kapplinger 2009 PMID: 19716085, Lieve 2013 PMID: 23631430). It is possible that there may be some overlap in the number of individuals from both groups. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 53090) and has been identified in 0.001% (1/112294 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies support an impact on protein function (Mousavi Nik 2015 PMID: 25705178, Moreno 2017 PMID: 28739325) and computational prediction tools and conservation are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LQTS. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3, PS3_Supporting. (less)
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Likely pathogenic
(Jan 20, 2014)
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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: SCV000280161.1
First in ClinVar: May 29, 2016 Last updated: May 29, 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.Asp242Asn Given the case data, absence in controls, and other disease-associated variants at the same and nearby residues, we consider this variant likely disease causing. The variant has been seen in at least nine unrelated cases who underwent LQTS sequencing and likely had LQTS, including two with clear reported LQTS. There is at least weak segregation in one family. Itoh et al (1998) observed the variant in one of 31 Japanese probands with long QT syndrome who underwent analysis of KCNQ1. The authors note that the variant cosegregated with disease but no specifics are provided. Splawski et al (2000) observed the variant in 1 of 262 unrelated patients with long QT who underwent analysis of KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2. Patients were ascertained in Europe and North America (may overlap with reports by Priori's group, the US long QT registry, the international long QT registry). No ancestry, segregation, or individual phenotype data was provided. Tester et al (2005) observed the variant in 1 of 541 cases. This publication is a compendium of variants identified in cases referred to Dr. Ackerman's research lab for long QT genetic testing. No individual clinical or segregation data was provided. Of note when considering this paper, it is likely that ~25% of patients in this cohort did not actually have long QT syndrome (based on the reported yield). The variant was reported in 4 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Those cases likely overlap with the data in Kapa et al (2009) and Giudicessi et al (2012) since these are all from Ackerman's group and use data from his cohort and from the Familion cohort. Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). The variant was reported in 3 (possibly related) long QT patients included in a study on genotype-phenotype correlations in KCNQ1 (Moss et al 2007). This study included 600 carriers of KCNQ1 variants from 101 families. Subjects were "drawn from the US portion of the International LQTS Registry (n¡425), the Netherlands’ LQTS Registry (n¡93), and the Japanese LQTS Registry (n¡82)" so there may be overlap with other publications from those groups. Given that and the author list, it is likely these cases are redundant with prior reports and with a later similar paper by the same group (Jons et al 2009). The variant was also reported by Lieve et al (2013) in 2 of 855 consecutive unrelated patients referred to GeneDx for long QT syndrome genetic testing (which included sequencing of KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, CACNA1C, KCNJ2, CAV3, and SCN4B). Their overall yield was 30%, suggesting that less than half of the tested individuals had long QT syndrome. Other variants have been reported in association with disease at this codon (Asp242Tyr (Jons et al 2009, Lieve et al 2013)) and nearby codons (p.V241G (Kapplinger et al 2009), R243C(>10 publications), R243P(Kapplinger et al 2009), R243S (Jons et al 2009). The variant is in the S4-S5 loop (Tester et al 2005). The variant was reported online in 1 of 57,641 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 16, 2015). Specifically, the variant was observed in 1 of 31,876. The phenotype of that individual is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). (less)
Number of individuals with the variant: 10
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Likely pathogenic
(Jul 14, 2017)
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no assertion criteria provided
Method: research
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Wolff-Parkinson-White pattern
Affected status: yes
Allele origin:
inherited
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Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Study: Candidate_variants_in_patients_with_ Wolff-Parkinson-White Syndrome
Accession: SCV000678353.1 First in ClinVar: Jun 02, 2018 Last updated: Jun 02, 2018 |
Comment:
This variant was identified in an individual with Wolff-Parkinson-White syndrome
Number of individuals with the variant: 1
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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: SCV000089257.3
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:9799083;PMID:15840476;PMID:19716085;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:9799083;PMID:15840476;PMID:19716085;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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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 |
Inactivation of KCNQ1 potassium channels reveals dynamic coupling between voltage sensing and pore opening. | Hou P | Nature communications | 2017 | PMID: 29167462 |
D242N, a K(V)7.1 LQTS mutation uncovers a key residue for I(Ks) voltage dependence. | Moreno C | Journal of molecular and cellular cardiology | 2017 | PMID: 28739325 |
Compound Mutations Cause Increased Cardiac Events in Children with Long QT Syndrome: Can the Sequence Homology-Based Tools be Applied for Prediction of Phenotypic Severity? | Izumi G | Pediatric cardiology | 2016 | PMID: 27041096 |
Cellular mechanisms of mutations in Kv7.1: auditory functions in Jervell and Lange-Nielsen syndrome vs. Romano-Ward syndrome. | Mousavi Nik A | Frontiers in cellular neuroscience | 2015 | PMID: 25705178 |
Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. | Lieve KV | Genetic testing and molecular biomarkers | 2013 | PMID: 23631430 |
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 |
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. | Tester DJ | Heart rhythm | 2005 | PMID: 15840476 |
KCNQ1 gene mutations and the respective genotype-phenotype correlations in the long QT syndrome. | Herbert E | Medical science monitor : international medical journal of experimental and clinical research | 2002 | PMID: 12388934 |
Genomic organization and mutational analysis of KVLQT1, a gene responsible for familial long QT syndrome. | Itoh T | Human genetics | 1998 | PMID: 9799083 |
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Text-mined citations for rs199472712 ...
HelpRecord last updated May 08, 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.