ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.1556G>A (p.Arg519His)
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(8); 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.1556G>A (p.Arg519His)
Variation ID: 67038 Accession: VCV000067038.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2768885 (GRCh38) [ NCBI UCSC ] 11: 2790115 (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 Feb 14, 2024 Jul 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.1556G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Arg519His missense NM_001406836.1:c.1460G>A NP_001393765.1:p.Arg487His missense NM_001406837.1:c.1286G>A NP_001393766.1:p.Arg429His missense NM_001406838.1:c.1016G>A NP_001393767.1:p.Arg339His missense NM_181798.2:c.1175G>A NP_861463.1:p.Arg392His missense NR_040711.2:n.1449G>A NC_000011.10:g.2768885G>A NC_000011.9:g.2790115G>A NG_008935.1:g.328895G>A LRG_287:g.328895G>A LRG_287t1:c.1556G>A LRG_287p1:p.Arg519His LRG_287t2:c.1175G>A LRG_287p2:p.Arg392His - Protein change
- R519H, R392H, R429H, R339H, R487H
- Other names
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- Canonical SPDI
- NC_000011.10:2768884: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) 0.00001
Exome Aggregation Consortium (ExAC) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
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
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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 | 2506 |
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 24, 2018 | RCV000057596.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 21, 2022 | RCV000543065.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 24, 2017 | RCV001104917.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 24, 2017 | RCV001106072.12 | |
Likely benign (1) |
criteria provided, single submitter
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Aug 24, 2017 | RCV001104916.12 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 2, 2023 | RCV000988473.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 26, 2023 | RCV001841670.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 11, 2023 | RCV003390759.4 |
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
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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
(Aug 24, 2018)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000863169.1
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
Number of individuals with the variant: 1
Sex: mixed
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Likely benign
(Aug 24, 2017)
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criteria provided, single submitter
Method: clinical testing
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Short QT syndrome type 2
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001261822.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Uncertain significance
(Aug 24, 2017)
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criteria provided, single submitter
Method: clinical testing
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Jervell and Lange-Nielsen syndrome 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001261823.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Aug 24, 2017)
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criteria provided, single submitter
Method: clinical testing
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Atrial fibrillation, familial, 3
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001263103.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Aug 24, 2017)
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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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Illumina Laboratory Services, Illumina
Accession: SCV001263104.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Jun 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001138206.2
First in ClinVar: Jan 09, 2020 Last updated: Jun 03, 2023 |
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Uncertain significance
(Apr 21, 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: SCV000627378.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 519 of the KCNQ1 protein (p.Arg519His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 519 of the KCNQ1 protein (p.Arg519His). This variant is present in population databases (rs199472788, gnomAD 0.006%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 14661677, 19841300, 26118460). ClinVar contains an entry for this variant (Variation ID: 67038). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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
(Jul 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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KCNQ1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004120898.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The KCNQ1 c.1556G>A variant is predicted to result in the amino acid substitution p.Arg519His. This variant was reported in an individual with long QT syndrome … (more)
The KCNQ1 c.1556G>A variant is predicted to result in the amino acid substitution p.Arg519His. This variant was reported in an individual with long QT syndrome (Itoh et al 2015. PubMed ID: 26118460). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-2790115-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(May 26, 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: SCV001355442.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 519 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with histidine at codon 519 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). This variant is found within a highly conserved region of the c-terminal cytoplasmic domain. Rare nontruncating variants in this region (a.a. 509-575) have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant causes a reduction in channel peak current density in transfected cells (PMID: 34930020). This variant has been reported in three unrelated individuals affected with long QT syndrome (PMID: 26118460), as well as in two healthy individuals (PMID: 19841300, 14661677). This variant has been identified in 7/282764 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, 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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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: SCV000089115.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported in the following publications (PMID:14661677;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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Arrhythmia Variant Associations and Reclassifications in the eMERGE-III Sequencing Study. | Glazer AM | Circulation | 2022 | PMID: 34930020 |
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 |
A Common Mutation of Long QT Syndrome Type 1 in Japan. | Itoh H | Circulation journal : official journal of the Japanese Circulation Society | 2015 | PMID: 26118460 |
Tox-database.net: a curated resource for data describing chemical triggered in vitro cardiac ion channels inhibition. | Polak S | BMC pharmacology & toxicology | 2012 | PMID: 22947121 |
Paralogous annotation of disease-causing variants in long QT syndrome genes. | Ware JS | Human mutation | 2012 | PMID: 22581653 |
Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. | Kapa S | Circulation | 2009 | PMID: 19841300 |
The single nucleotide polymorphisms of I(Ks) potassium channel genes and their association with atrial fibrillation in a Chinese population. | Zeng Z | Cardiology | 2007 | PMID: 17016049 |
Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome. | Ackerman MJ | Mayo Clinic proceedings | 2003 | PMID: 14661677 |
Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. | Krinsley JS | Mayo Clinic proceedings | 2003 | PMID: 14661676 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=KCNQ1 | - | - | - | - |
Text-mined citations for rs199472788 ...
HelpRecord last updated Mar 23, 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.