ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.532G>A (p.Ala178Thr)
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.532G>A (p.Ala178Thr)
Variation ID: 53061 Accession: VCV000053061.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2570682 (GRCh38) [ NCBI UCSC ] 11: 2591912 (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 Dec 6, 2014 Apr 15, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.532G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Ala178Thr missense NM_001406836.1:c.532G>A NP_001393765.1:p.Ala178Thr missense NM_001406837.1:c.262G>A NP_001393766.1:p.Ala88Thr missense NM_181798.2:c.151G>A NP_861463.1:p.Ala51Thr missense NR_040711.2:n.425G>A NC_000011.10:g.2570682G>A NC_000011.9:g.2591912G>A NG_008935.1:g.130692G>A LRG_287:g.130692G>A LRG_287t1:c.532G>A LRG_287p1:p.Ala178Thr LRG_287t2:c.151G>A LRG_287p2:p.Ala51Thr P51787:p.Ala178Thr - Protein change
- A178T, A51T, A88T
- Other names
- p.A178T:GCC>ACC
- Canonical SPDI
- NC_000011.10:2570681: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00002
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
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 |
1648 | 2513 |
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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not provided (1) |
no classification provided
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- | RCV000057692.5 | |
Pathogenic (2) |
criteria provided, single submitter
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Dec 27, 2023 | RCV000148553.15 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2023 | RCV000182081.16 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 6, 2022 | RCV000244422.4 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 11, 2020 | RCV001028063.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 19, 2019 | RCV001258060.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 7, 2022 | RCV003591642.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 29, 2024 | RCV003989306.1 |
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
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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Likely pathogenic
(Aug 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
Jervell and Lange-Nielsen syndrome 1
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434891.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
This c.532G>A (p.Ala178Thr) variant in the KCNQ1 gene has been reported in patients with Long QT syndrome (PMID: 9024139, 22456477, 10973849). This variant has an … (more)
This c.532G>A (p.Ala178Thr) variant in the KCNQ1 gene has been reported in patients with Long QT syndrome (PMID: 9024139, 22456477, 10973849). This variant has an ultra-low minor allele frequency in the gnomAD database (1/248870). The Ala178 residue is highly conserved and multiple computational algorithms predict a deleterious effect of the p.Ala178Thr change. In vitro functional studies suggest this variant disrupts channel trafficking (PMID: 24912595). Therefore, the c.532G>A (p.Ala178Thr) variant in the KCNQ1 gene is classified as likely pathogenic. (less)
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Likely pathogenic
(Feb 27, 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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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369915.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1_MOD,PM2,PS4_SUP,PP3.
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Likely pathogenic
(Mar 30, 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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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002051661.3
First in ClinVar: Jan 08, 2022 Last updated: Feb 11, 2022 |
Comment:
PS3, PM2, PM1, PP3
Secondary finding: yes
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Likely pathogenic
(May 06, 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: SCV000320309.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.A178T variant (also known as c.532G>A), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide … (more)
The p.A178T variant (also known as c.532G>A), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 532. The alanine at codon 178 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in individuals reported to have long QT syndrome (Tanaka T et al. Circulation. 1997; 95(3):565-7 (reported as Ala49Thr); Jons C et al. J Cardiovasc Electrophysiol. 2009; 20(8):859-65; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). In one study, this alteration was detected as compound heterozygous with a frameshift alteration in a severely affected child, while relatives who were heterozygous for this alteration was unaffected. In the same study, the p.A178T alteration was reported to have moderate impact on channel trafficking and function and moderate dominant negative effect (Harmer SC et al. Biochem J. 2014; 462(1):133-42). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Feb 23, 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: SCV000234384.15
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Identified in several patients with LQTS referred for genetic testing at GeneDx and in published literature (Tanaka et al., 1997; Splawski et al., 2000; Jons … (more)
Identified in several patients with LQTS referred for genetic testing at GeneDx and in published literature (Tanaka et al., 1997; Splawski et al., 2000; Jons et al., 2009; Kapplinger et al., 2009; Kwok et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant severely disrupts channel trafficking (Harmer et al., 2014; Mousavi et al., 2015); 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: 10973849, 25705178, 30530868, 22378279, 25637381, 22456477, 9024139, 12388934, 19490272, 26546361, 28991257, 19716085, 32368696, 34426522, 24912595) (less)
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Pathogenic
(Mar 29, 2024)
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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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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004808128.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Jun 11, 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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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557903.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene, however only missense causing short QT syndrome has been reported with a gain of function mechanism (OMIM). (N) 0104 - Dominant Negative is a mechanism of disease for this gene. Both truncating variants escaping NMD, and missense have been proven to cause a dominant negative effect (OMIM, PMID: 19632626). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Recessive disease is mostly caused by biallelic NMD variants (PMID: 28438721). (N) 0112 - Variants in this gene causing long QT syndrome are known to have reduced penetrance (GeneReviews, OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine (exon 3). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif, (S2 to S3 intracellular linker within the ion transporter domain; NCBI). (N) 0704 - Comparable variant (p.Ala178Pro) has low previous evidence for pathogenicity in patients with long QT syndrome (ClinVar, LOVD, PMID: 19490272). (P) 0801 - Strong previous evidence of pathogenicity in unrelated heterozygous and homozygous individuals with long QT syndrome. Heterozygous carriers have been reported as both symptomatic and asymptomatic (ClinVar, LOVD, PMID: 28438721, PMID: 19716085, PMID: 9024139, PMID: 30530868) (P) 1002 - Moderate functional evidence supporting abnormal protein function. Transfected cells demonstrated impaired protein localization and shifts to depolarized potentials (PMID: 24912595). (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Likely pathogenic
(Nov 07, 2022)
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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: SCV004358374.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces alanine with threonine at codon 178 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces alanine with threonine at codon 178 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant results in the protein retention in the endoplasmic reticulum and a reduced cell-surface expression of the potassium channel due to the trafficking defects (PMID: 24912595). This variant has been reported in at least ten unrelated individuals affected with long QT syndrome (PMID: 9024139, 10973849, 19490272, 19716085, 22456477, 28438721, 29033053, 30530868, 32893267). Of these, 3 affected individuals were homozygous for this variant. Two related homozygous individuals were affected with Long QT syndrome at childhood while one heterozygous individual from the same consanguineous family was unaffected at the age of 39 (PMID: 28438721). Another unrelated homozygous individual was affected with autosomal recessive Romano-Ward Syndrome (PMID: 29033053). This variant has also been observed in compound heterozygous state with a pathogenic truncation variant in a child affected with severe phenotype (PMID: 24912595). This variant has been identified in 1/248870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Pathogenic
(Dec 27, 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: SCV000074088.13
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 178 of the KCNQ1 protein (p.Ala178Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 178 of the KCNQ1 protein (p.Ala178Thr). This variant is present in population databases (rs120074177, gnomAD 0.003%). This missense change has been observed in individuals with long QT syndrome (PMID: 9024139, 10973849, 19716085, 22456477). ClinVar contains an entry for this variant (Variation ID: 53061). 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: 24912595). This variant disrupts the p.Ala178 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17470695). 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
(Apr 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004010037.6
First in ClinVar: Jul 16, 2023 Last updated: Apr 15, 2024 |
Comment:
KCNQ1: PS2, PM5, PS4:Moderate, PM2:Supporting, PP1
Number of individuals with the variant: 2
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Uncertain significance
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190266.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 |
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Pathogenic
(Feb 05, 2020)
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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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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001190839.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
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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: SCV000089211.3
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:9024139;PMID:19716085;PMID:22378279). 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:9024139;PMID:19716085;PMID:22378279). 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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Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 32893267 |
Clinical and genetic profile of congenital long QT syndrome in Hong Kong: a 20-year experience in paediatrics. | Kwok SY | Hong Kong medical journal = Xianggang yi xue za zhi | 2018 | PMID: 30530868 |
Identification and characterization of a novel recessive KCNQ1 mutation associated with Romano-Ward Long-QT syndrome in two Iranian families. | Zafari Z | Journal of electrocardiology | 2017 | PMID: 29033053 |
Clinical profile and mutation spectrum of long QT syndrome in Saudi Arabia: The impact of consanguinity. | Al-Hassnan ZN | Heart rhythm | 2017 | PMID: 28438721 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
Cellular mechanisms underlying the increased disease severity seen for patients with long QT syndrome caused by compound mutations in KCNQ1. | Harmer SC | The Biochemical journal | 2014 | PMID: 24912595 |
Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to β-blocker therapy in type 1 long-QT syndrome. | Barsheshet A | Circulation | 2012 | PMID: 22456477 |
High prevalence of genetic variants previously associated with LQT syndrome in new exome data. | Refsgaard L | European journal of human genetics : EJHG | 2012 | PMID: 22378279 |
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 |
Mutation in the S3 segment of KCNQ1 results in familial lone atrial fibrillation. | Das S | Heart rhythm | 2009 | PMID: 19632626 |
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 |
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. | Splawski I | Circulation | 2000 | PMID: 10973849 |
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 rs120074177 ...
HelpRecord last updated Apr 15, 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.