ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.1571T>G (p.Val524Gly)
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.
Pathogenic(2); Uncertain significance(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.1571T>G (p.Val524Gly)
Variation ID: 52994 Accession: VCV000052994.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2768900 (GRCh38) [ NCBI UCSC ] 11: 2790130 (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 Apr 20, 2024 Oct 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.1571T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Val524Gly missense NM_001406836.1:c.1475T>G NP_001393765.1:p.Val492Gly missense NM_001406837.1:c.1301T>G NP_001393766.1:p.Val434Gly missense NM_001406838.1:c.1031T>G NP_001393767.1:p.Val344Gly missense NM_181798.2:c.1190T>G NP_861463.1:p.Val397Gly missense NR_040711.2:n.1464T>G NC_000011.10:g.2768900T>G NC_000011.9:g.2790130T>G NG_008935.1:g.328910T>G LRG_287:g.328910T>G LRG_287t1:c.1571T>G LRG_287p1:p.Val524Gly LRG_287t2:c.1190T>G LRG_287p2:p.Val397Gly P51787:p.Val524Gly - Protein change
- V524G, V397G, V344G, V434G, V492G
- Other names
- p.V524G:GTG>GGG
- Canonical SPDI
- NC_000011.10:2768899:T:G
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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.
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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 |
1718 | 2652 |
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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Pathogenic (1) |
criteria provided, single submitter
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Oct 30, 2023 | RCV000046000.13 | |
not provided (1) |
no classification provided
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- | RCV000057599.4 | |
Pathogenic (3) |
criteria provided, single submitter
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Sep 8, 2022 | RCV000182201.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 7, 2019 | RCV004017349.1 |
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
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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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Pathogenic
(Sep 08, 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: SCV000234504.13
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Identified in patients with LQTS referred for genetic testing at GeneDx, and in the published literature (Zareba et al., 2003; Tester et al., 2005; Kapplinger … (more)
Identified in patients with LQTS referred for genetic testing at GeneDx, and in the published literature (Zareba et al., 2003; Tester et al., 2005; Kapplinger et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies with low cytometry of V524G-transfected HEK293 cells showed significantly reduced surface trafficking compared to wild-type (Kanner et al., 2020); 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: 23392653, 25525159, 15466642, 15840476, 19716085, 17470695, 19841300, 22949429, 33198487, 23728945, 22581653, 14678125, 33169015) (less)
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Pathogenic
(Oct 30, 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: SCV000074013.12
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 524 of the KCNQ1 protein (p.Val524Gly). … (more)
This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 524 of the KCNQ1 protein (p.Val524Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant long QT syndrome (PMID: 14678125, 15840476, 17470695, 22949429). This variant has been reported in individual(s) with autosomal recessive long QT syndrome without hearing loss typically associated with autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 23392653); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 52994). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Jun 07, 2019)
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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: SCV004849043.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The c.1571T>G (p.V524G) alteration is located in exon 12 (coding exon 12) of the KCNQ1 gene. This alteration results from a T to G substitution … (more)
The c.1571T>G (p.V524G) alteration is located in exon 12 (coding exon 12) of the KCNQ1 gene. This alteration results from a T to G substitution at nucleotide position 1571, causing the valine (V) at amino acid position 524 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001922124.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956877.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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: SCV000089118.3
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:14678125;PMID:15466642;PMID:15840476;PMID:19716085;PMID:19841300;PMID:17470695). 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:14678125;PMID:15466642;PMID:15840476;PMID:19716085;PMID:19841300;PMID:17470695). 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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Prevalence and potential genetic determinants of sensorineural deafness in KCNQ1 homozygosity and compound heterozygosity. | Giudicessi JR | Circulation. Cardiovascular genetics | 2013 | PMID: 23392653 |
Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome. | Giudicessi JR | Circulation. Cardiovascular genetics | 2012 | PMID: 22949429 |
Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. | Kapa S | Circulation | 2009 | PMID: 19841300 |
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 |
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 |
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. | Tester DJ | Heart rhythm | 2005 | PMID: 15840476 |
Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. | Choi G | Circulation | 2004 | PMID: 15466642 |
Location of mutation in the KCNQ1 and phenotypic presentation of long QT syndrome. | Zareba W | Journal of cardiovascular electrophysiology | 2003 | PMID: 14678125 |
Text-mined citations for rs199472790 ...
HelpRecord last updated May 01, 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.