ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.1520G>A (p.Arg507Gln)
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.1520G>A (p.Arg507Gln)
Variation ID: 519296 Accession: VCV000519296.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2768849 (GRCh38) [ NCBI UCSC ] 11: 2790079 (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 14, 2018 Apr 20, 2024 Dec 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.1520G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Arg507Gln missense NM_001406836.1:c.1424G>A NP_001393765.1:p.Arg475Gln missense NM_001406837.1:c.1250G>A NP_001393766.1:p.Arg417Gln missense NM_001406838.1:c.980G>A NP_001393767.1:p.Arg327Gln missense NM_181798.2:c.1139G>A NP_861463.1:p.Arg380Gln missense NR_040711.2:n.1413G>A NC_000011.10:g.2768849G>A NC_000011.9:g.2790079G>A NG_008935.1:g.328859G>A LRG_287:g.328859G>A LRG_287t1:c.1520G>A LRG_287p1:p.Arg507Gln LRG_287t2:c.1139G>A LRG_287p2:p.Arg380Gln - Protein change
- R380Q, R507Q, R327Q, R417Q, R475Q
- Other names
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- Canonical SPDI
- NC_000011.10:2768848: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) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 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
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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
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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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Uncertain significance (1) |
criteria provided, single submitter
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Jul 20, 2021 | RCV000619748.10 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2023 | RCV000690171.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 16, 2023 | RCV001841801.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 25, 2020 | RCV002470932.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 11, 2021 | RCV002499001.8 |
Submissions - Germline
Classification
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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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Uncertain significance
(Jul 20, 2021)
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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: SCV000737651.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R507Q variant (also known as c.1520G>A), located in coding exon 12 of the KCNQ1 gene, results from a G to A substitution at nucleotide … (more)
The p.R507Q variant (also known as c.1520G>A), located in coding exon 12 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1520. The arginine at codon 507 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a hypertrophic cardiomyopathy cohort and a control cohort; however, clinical details were limited (Lopes LR et al. J. Med. Genet. 2013 Apr; 50(4):228-39; Kapplinger JD et al. J Cardiovasc Transl Res 2015 Apr; 8(3):187-97). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(May 25, 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: SCV002768723.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS-3B. 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 VUS-3B. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene (OMIM). (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0112 - Variants in this gene are known to have reduced penetrance (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (12 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (3 Heterozygotes, 0 homozygotes). (N) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (KCNQ1 channel: PDB, decipher). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. Reported in 1 HCM patient (PMID:23396983) and VUS (ClinVar). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Uncertain significance
(Oct 11, 2021)
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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: SCV002809956.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Feb 16, 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: SCV002053317.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with glutamine at codon 507 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 507 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 an individual affected with hypertrophic cardiomyopathy (PMID: 23396983). This variant has been identified in 12/251374 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
(Oct 03, 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: SCV000817850.5
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 507 of the KCNQ1 protein (p.Arg507Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 507 of the KCNQ1 protein (p.Arg507Gln). This variant is present in population databases (rs369571296, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of KCNQ1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 519296). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. 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
(Dec 01, 2023)
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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: SCV004836451.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces arginine with glutamine at codon 507 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 507 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 an individual affected with hypertrophic cardiomyopathy (PMID: 23396983). This variant has been identified in 12/251374 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: 8
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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 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 |
Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. | Lopes LR | Journal of medical genetics | 2013 | PMID: 23396983 |
Text-mined citations for rs369571296 ...
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.