ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.1355G>A (p.Arg452Gln)
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.
Uncertain significance(12); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000218.3(KCNQ1):c.1355G>A (p.Arg452Gln)
Variation ID: 67030 Accession: VCV000067030.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2588816 (GRCh38) [ NCBI UCSC ] 11: 2610046 (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 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.1355G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Arg452Gln missense NM_001406836.1:c.1259G>A NP_001393765.1:p.Arg420Gln missense NM_001406837.1:c.1085G>A NP_001393766.1:p.Arg362Gln missense NM_001406838.1:c.815G>A NP_001393767.1:p.Arg272Gln missense NM_181798.2:c.974G>A NP_861463.1:p.Arg325Gln missense NR_040711.2:n.1248G>A NC_000011.10:g.2588816G>A NC_000011.9:g.2610046G>A NG_008935.1:g.148826G>A LRG_287:g.148826G>A LRG_287t1:c.1355G>A LRG_287p1:p.Arg452Gln LRG_287t2:c.974G>A LRG_287p2:p.Arg325Gln - Protein change
- R452Q, R325Q, R272Q, R362Q, R420Q
- Other names
- p.R452Q:CGG>CAG
- Canonical SPDI
- NC_000011.10:2588815: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00014
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
The Genome Aggregation Database (gnomAD) 0.00025
Exome Aggregation Consortium (ExAC) 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
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
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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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Uncertain significance (2) |
criteria provided, single submitter
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Aug 17, 2023 | RCV000057583.14 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 13, 2023 | RCV000246256.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000337547.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000355198.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000284895.13 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 11, 2024 | RCV000297971.22 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000398200.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 3, 2022 | RCV000764975.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 17, 2020 | RCV001255594.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 27, 2023 | RCV001841666.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 15, 2023 | RCV003448257.1 | |
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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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Uncertain significance
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Jervell and Lange-Nielsen Syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000370300.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Uncertain significance
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Short QT Syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000370298.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Uncertain significance
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Familial Atrial Fibrillation
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000370297.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Uncertain significance
(Jun 14, 2016)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000370299.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Uncertain significance
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Romano-Ward Syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000370296.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Uncertain significance
(Feb 03, 2022)
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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: SCV000896152.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Likely benign
(Mar 13, 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: SCV000320292.7
First in ClinVar: Oct 02, 2016 Last updated: Apr 15, 2023 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(May 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Atrial fibrillation, familial, 3
Long QT syndrome 1 Short QT syndrome type 2
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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New York Genome Center
Accession: SCV004176190.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The c.1355G>A p.(Arg452Gln) missense variant identified in the KCNQ1 gene has been reported in the literature in individuals affected with Arrhythmia and long QT syndrome … (more)
The c.1355G>A p.(Arg452Gln) missense variant identified in the KCNQ1 gene has been reported in the literature in individuals affected with Arrhythmia and long QT syndrome type 1 as well as in healthy controls (PMID: 19841300, 26318259, 29197658). The c.1355G>A variant has been deposited in ClinVar with conflicting interpretations of pathogenicity by multiple submitters, including ten Uncertain significance and one Likely benign entry [ClinVar ID: 67030]. The variant has an allele frequency of 0.0000951 (56 out of 588,570 heterozygous alleles, no homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2,TOPMed Freeze 8). The c.1355G>A The c.1355G>A variant is located in exon 10 of this 16-exon gene and is predicted to replace a moderately conserved arginine residue with glutamine at position 452 of the encoded protein. In silico predictions are in favor of the variants damaging effect [REVEL = 0.644]; however, functional studies to support or refute these predictions have not been reported. Due to the lack of compelling evidence for its pathogenicity, the c.1355G>Ap.(Arg452Gln) missense variant identified in the KCNQ1 gene is reported as a Variant of Uncertain Significance. (less)
Clinical Features:
Cardiomyopathy (present)
Secondary finding: no
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Uncertain significance
(Jan 02, 2024)
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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: SCV000543296.9
First in ClinVar: Dec 06, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 452 of the KCNQ1 protein (p.Arg452Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 452 of the KCNQ1 protein (p.Arg452Gln). This variant is present in population databases (rs145229963, gnomAD 0.02%). This missense change has been observed in individual(s) with KCNQ1-related conditions (PMID: 26318259). ClinVar contains an entry for this variant (Variation ID: 67030). 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 not expected to disrupt KCNQ1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jan 27, 2023)
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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: SCV000913736.5
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with glutamine at codon 452 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with glutamine at codon 452 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a proband affected with long QT syndrome (PMID: 26318259). This variant has been identified in 31/281090 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Jan 11, 2024)
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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: SCV004836427.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces arginine with glutamine at codon 452 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with glutamine at codon 452 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 31/281090 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 22
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Uncertain significance
(Aug 17, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001432100.1
First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020 |
Comment:
Variant summary: KCNQ1 c.1355G>A (p.Arg452Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: KCNQ1 c.1355G>A (p.Arg452Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 283970 control chromosomes (gnomAD and publication data). The observed variant frequency is approximately 1.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNQ1 causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is benign. c.1355G>A has been reported in the literature in individuals affected with Arrhythmia and long QT syndrome type 1 as well as in healthy controls (Kapa_2009, Ruwald_2016, Clemens_2018, Li_2019). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Uncertain significance
(Aug 17, 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: SCV000234492.14
First in ClinVar: Jul 05, 2015 Last updated: Nov 25, 2023 |
Comment:
Reported in two individuals from one family with LQTS (Ruwald et al., 2020) and present in control cohorts (Kapa et al., 2009); In silico analysis … (more)
Reported in two individuals from one family with LQTS (Ruwald et al., 2020) and present in control cohorts (Kapa et al., 2009); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19841300, 22581653, 25854863, 22949429, 29197658, 31696929, 26318259) (less)
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not provided
(-)
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no classification provided
Method: literature only
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not provided
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089102.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported in the following publications (PMID:19841300).
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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 frequencies of KCNQ1, KCNH2, and SCN5A in a Chinese inherited arrhythmia cohort and other disease cohorts undergoing genetic testing. | Li X | Annals of human genetics | 2020 | PMID: 31696929 |
Using the genome aggregation database, computational pathogenicity prediction tools, and patch clamp heterologous expression studies to demote previously published long QT syndrome type 1 mutations from pathogenic to benign. | Clemens DJ | Heart rhythm | 2018 | PMID: 29197658 |
Stop-codon and C-terminal nonsense mutations are associated with a lower risk of cardiac events in patients with long QT syndrome type 1. | Ruwald MH | Heart rhythm | 2016 | PMID: 26318259 |
Enhancing the Predictive Power of Mutations in the C-Terminus of the KCNQ1-Encoded Kv7.1 Voltage-Gated Potassium Channel. | Kapplinger JD | Journal of cardiovascular translational research | 2015 | PMID: 25854863 |
Bayesian models for syndrome- and gene-specific probabilities of novel variant pathogenicity. | Ruklisa D | Genome medicine | 2015 | PMID: 25649125 |
Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. | Kapa S | Circulation | 2009 | PMID: 19841300 |
Text-mined citations for rs145229963 ...
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.