ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.513C>A (p.Tyr171Ter)
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.513C>A (p.Tyr171Ter)
Variation ID: 265209 Accession: VCV000265209.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2570663 (GRCh38) [ NCBI UCSC ] 11: 2591893 (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 Apr 23, 2017 Apr 20, 2024 Jan 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.513C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Tyr171Ter nonsense NM_001406836.1:c.513C>A NP_001393765.1:p.Tyr171Ter nonsense NM_001406837.1:c.243C>A NP_001393766.1:p.Tyr81Ter nonsense NM_181798.2:c.132C>A NP_861463.1:p.Tyr44Ter nonsense NR_040711.2:n.406C>A NC_000011.10:g.2570663C>A NC_000011.9:g.2591893C>A NG_008935.1:g.130673C>A LRG_287:g.130673C>A LRG_287t1:c.513C>A LRG_287p1:p.Tyr171Ter LRG_287t2:c.132C>A LRG_287p2:p.Tyr44Ter - Protein change
- Y171*, Y44*, Y81*
- Other names
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- Canonical SPDI
- NC_000011.10:2570662:C: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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0.00020 (T)
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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 |
1696 | 2580 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Likely pathogenic (2) |
criteria provided, single submitter
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Jun 24, 2022 | RCV000477871.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 8, 2017 | RCV000617940.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 17, 2024 | RCV000814153.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 21, 2023 | RCV003591726.1 |
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
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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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Likely pathogenic
(Jun 24, 2022)
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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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MGZ Medical Genetics Center
Accession: SCV002580040.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Jun 08, 2017)
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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: SCV000738002.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.Y171* pathogenic mutation (also known as c.513C>A), located in coding exon 3 of the KCNQ1 gene, results from a C to A substitution at … (more)
The p.Y171* pathogenic mutation (also known as c.513C>A), located in coding exon 3 of the KCNQ1 gene, results from a C to A substitution at nucleotide position 513. This changes the amino acid from a tyrosine to a stop codon within coding exon 3. This alteration has been reported in a sudden cardiac arrest/death cohort (Li MH et al. Human Genomics, 2015 9:15). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jan 17, 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: SCV000954554.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr171*) in the KCNQ1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Tyr171*) in the KCNQ1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 11216980, 12051962, 14678125, 26187847). ClinVar contains an entry for this variant (Variation ID: 265209). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 21, 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: SCV004358372.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 3 of the KCNQ1 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 3 of the KCNQ1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has shown that this variant results in undetectable expression of KCNQ1 in RNA and protein levels and no functional potassium current in transfected cells (PMID: 33504163). This variant has been reported in at least three unrelated individuals affected with long QT syndrome (PMID: 14678125, 32893267), in an individual affected with sudden cardiac arrest or death (PMID: 26187847), and in an asymptomatic individual (PMID: 33504163). A different nucleotide change (c.513C>G) leading to the same nonsense variant has been determined to be pathogenic (ClinVar variation ID 53056). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jan 08, 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: SCV004825203.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This variant changes 1 nucleotide in exon 3 of the KCNQ1 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 3 of the KCNQ1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has shown that this variant results in undetectable expression of KCNQ1 in RNA and protein levels and no functional potassium current in transfected cells (PMID: 33504163). This variant has been reported in at least three unrelated individuals affected with long QT syndrome (PMID: 14678125, 32893267), in an individual affected with sudden cardiac arrest or death (PMID: 26187847), and in an asymptomatic individual (PMID: 33504163). A different nucleotide change (c.513C>G) leading to the same nonsense variant has been determined to be pathogenic (ClinVar variation ID 53056). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 3
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Pathogenic
(Feb 25, 2016)
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no assertion criteria provided
Method: research
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Long QT syndrome 1
Affected status: yes
Allele origin:
maternal
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536844.1 First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017 |
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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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Suppression-Replacement KCNQ1 Gene Therapy for Type 1 Long QT Syndrome. | Dotzler SM | Circulation | 2021 | PMID: 33504163 |
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 |
Utility and limitations of exome sequencing as a genetic diagnostic tool for conditions associated with pediatric sudden cardiac arrest/sudden cardiac death. | Li MH | Human genomics | 2015 | PMID: 26187847 |
The genetic basis of long QT and short QT syndromes: a mutation update. | Hedley PL | Human mutation | 2009 | PMID: 19862833 |
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 |
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. | Tester DJ | Heart rhythm | 2005 | PMID: 15840476 |
Location of mutation in the KCNQ1 and phenotypic presentation of long QT syndrome. | Zareba W | Journal of cardiovascular electrophysiology | 2003 | PMID: 14678125 |
Compound heterozygous mutations in KvLQT1 cause Jervell and Lange-Nielsen syndrome. | Wang Z | Molecular genetics and metabolism | 2002 | PMID: 12051962 |
A founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics. | Piippo K | Journal of the American College of Cardiology | 2001 | PMID: 11216980 |
Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome. | Shalaby FY | Circulation | 1997 | PMID: 9323054 |
Text-mined citations for rs139042529 ...
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.