ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.860C>A (p.Ala287Glu)
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.860C>A (p.Ala287Glu)
Variation ID: 53118 Accession: VCV000053118.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2572925 (GRCh38) [ NCBI UCSC ] 11: 2594155 (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 Jan 30, 2015 May 12, 2024 Feb 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.860C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Ala287Glu missense NM_001406836.1:c.860C>A NP_001393765.1:p.Ala287Glu missense NM_001406837.1:c.590C>A NP_001393766.1:p.Ala197Glu missense NM_181798.2:c.479C>A NP_861463.1:p.Ala160Glu missense NR_040711.2:n.753C>A NC_000011.10:g.2572925C>A NC_000011.9:g.2594155C>A NG_008935.1:g.132935C>A LRG_287:g.132935C>A LRG_287t1:c.860C>A LRG_287p1:p.Ala287Glu LRG_287t2:c.479C>A LRG_287p2:p.Ala160Glu P51787:p.Ala287Glu - Protein change
- A287E, A160E, A197E
- Other names
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- Canonical SPDI
- NC_000011.10:2572924: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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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00008
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
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
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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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not provided (1) |
no classification provided
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- | RCV000057782.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 5, 2024 | RCV001316443.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 2, 2016 | RCV000618222.11 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2022 | RCV001588869.20 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 31, 2023 | RCV001841655.11 |
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
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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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Uncertain significance
(Dec 27, 2019)
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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: SCV001824021.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31737537, 32048431, 29197658, 16414944, 22581653, 23631430, 28491751) (less)
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Uncertain significance
(Jun 22, 2022)
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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: SCV001507062.2
First in ClinVar: Mar 14, 2021 Last updated: Mar 26, 2023 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 287 of the KCNQ1 protein … (more)
This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 287 of the KCNQ1 protein (p.Ala287Glu). This variant is present in population databases (rs199472735, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 16414944, 31737537). ClinVar contains an entry for this variant (Variation ID: 53118). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNQ1 function (PMID: 28491751). 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
(Oct 05, 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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000198429.6
First in ClinVar: Jan 30, 2015 Last updated: Apr 20, 2024 |
Comment:
The p.Ala287Glu variant in KCNQ1 has been reported in 2 individuals with Long QT syndrome (LQTS) (Napolitano 2006 PMID: 16414944, Marschall 2019 PMID: 31737537). This … (more)
The p.Ala287Glu variant in KCNQ1 has been reported in 2 individuals with Long QT syndrome (LQTS) (Napolitano 2006 PMID: 16414944, Marschall 2019 PMID: 31737537). This variant has not been reported in individuals with hearing loss or Jervell and Lange-Nielsen syndrome. It has also been identified in 0.011% (12/112954) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide inconclusive evidence regarding how this variant may impact protein function (Rothenberg 2016 PMID: 28491751); however, these types of assays may not accurately represent biological function. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3. (less)
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Uncertain significance
(Nov 02, 2016)
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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: SCV000737796.5
First in ClinVar: Apr 14, 2018 Last updated: Apr 20, 2024 |
Comment:
The c.860C>A (p.A287E) alteration is located in exon 6 (coding exon 6) of the KCNQ1 gene. This alteration results from a C to A substitution … (more)
The c.860C>A (p.A287E) alteration is located in exon 6 (coding exon 6) of the KCNQ1 gene. This alteration results from a C to A substitution at nucleotide position 860, causing the alanine (A) at amino acid position 287 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Aug 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002585268.10
First in ClinVar: Oct 22, 2022 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(May 31, 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: SCV000904481.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces alanine with glutamic acid at codon 287 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact … (more)
This missense variant replaces alanine with glutamic acid at codon 287 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 increased peak current amplitudes of the ion channels (PMID: 284917516). This variant has been reported in individuals affected with or suspected of long QT syndrome (PMID:16414944, 31737537). This variant has been identified in 13/250332 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
(Feb 05, 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: SCV004838790.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces alanine with glutamic acid at codon 287 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact … (more)
This missense variant replaces alanine with glutamic acid at codon 287 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 increased peak current amplitudes of the ion channels (PMID: 28491751). This variant has been reported in individuals affected with or suspected of long QT syndrome (PMID:16414944, 31737537). This variant has been identified in 13/250332 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: 12
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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: SCV000089301.3
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:16414944). 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:16414944). 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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Critical assessment of secondary findings in genes linked to primary arrhythmia syndromes. | Diebold I | Human mutation | 2020 | PMID: 32048431 |
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 |
Structural interplay of K(V)7.1 and KCNE1 is essential for normal repolarization and is compromised in short QT syndrome 2 (K(V)7.1-A287T). | Rothenberg I | HeartRhythm case reports | 2016 | PMID: 28491751 |
Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. | Napolitano C | JAMA | 2005 | PMID: 16414944 |
Text-mined citations for rs199472735 ...
HelpRecord last updated May 27, 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.