ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.484G>A (p.Val162Met)
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.484G>A (p.Val162Met)
Variation ID: 67077 Accession: VCV000067077.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2570634 (GRCh38) [ NCBI UCSC ] 11: 2591864 (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 Jun 1, 2016 Apr 20, 2024 Jan 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.484G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Val162Met missense NM_001406836.1:c.484G>A NP_001393765.1:p.Val162Met missense NM_001406837.1:c.214G>A NP_001393766.1:p.Val72Met missense NM_181798.2:c.103G>A NP_861463.1:p.Val35Met missense NR_040711.2:n.377G>A NC_000011.10:g.2570634G>A NC_000011.9:g.2591864G>A NG_008935.1:g.130644G>A LRG_287:g.130644G>A LRG_287t1:c.484G>A LRG_287p1:p.Val162Met LRG_287t2:c.103G>A LRG_287p2:p.Val35Met P51787:p.Val162Met - Protein change
- V162M, V35M, V72M
- Other names
- p.V162M:GTG>ATG
- Canonical SPDI
- NC_000011.10:2570633: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.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
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
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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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not provided (1) |
no classification provided
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- | RCV000057683.11 | |
Uncertain significance (2) |
criteria provided, single submitter
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Mar 31, 2016 | RCV000223780.15 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2024 | RCV000468709.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 2, 2019 | RCV000767079.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 27, 2023 | RCV001841682.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 28, 2018 | RCV003372615.2 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
(Mar 31, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000539458.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband, ExAC: 2/65476 European; ClinVar: 1 Pathogenic (less)
Method: Genome/Exome Filtration
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Uncertain significance
(Jan 27, 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: SCV001357590.4
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces valine with methionine at codon 162 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces valine with methionine at codon 162 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). An experimental study has shown that this variant does not affect channel function (PMID: 29330128). This variant has been reported in an individual referred for long QT genetic testing (PMID: 19716085). In a family affected with long QT syndrome, this variant did not segregate with disease, while a different variant in the KCNH2 gene segregated with disease in the family (PMID: 29330128). This variant has been identified in 6/280908 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
(Dec 13, 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: SCV004838748.1
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 valine with methionine at codon 162 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces valine with methionine at codon 162 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). An experimental study has shown that this variant does not affect channel function (PMID: 29330128). This variant has been reported in an individual referred for long QT genetic testing (PMID: 19716085). In a family affected with long QT syndrome, this variant did not segregate with disease, while a different variant in the KCNH2 gene segregated with disease in the family (PMID: 29330128). This variant has been identified in 6/280908 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: 11
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Uncertain significance
(Dec 28, 2018)
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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: SCV004080024.2
First in ClinVar: Oct 28, 2023 Last updated: Apr 20, 2024 |
Comment:
The c.484G>A (p.V162M) alteration is located in exon 3 (coding exon 3) of the KCNQ1 gene. This alteration results from a G to A substitution … (more)
The c.484G>A (p.V162M) alteration is located in exon 3 (coding exon 3) of the KCNQ1 gene. This alteration results from a G to A substitution at nucleotide position 484, causing the valine (V) at amino acid position 162 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Apr 02, 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: SCV000234598.13
First in ClinVar: Jul 05, 2015 Last updated: Apr 17, 2019 |
Comment:
Reported in one individual referred for LQTS genetic testing and was not observed in more than 2,600 reference alleles (Kapplinger et al., 2009); In silico … (more)
Reported in one individual referred for LQTS genetic testing and was not observed in more than 2,600 reference alleles (Kapplinger et al., 2009); 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: 22581653, 19716085, 19841300, 29330128, 30571187) (less)
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Uncertain significance
(Jan 24, 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: SCV000543291.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 162 of the KCNQ1 protein (p.Val162Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 162 of the KCNQ1 protein (p.Val162Met). This variant is present in population databases (rs199472692, gnomAD 0.005%). This missense change has been observed in individual(s) with Long QT syndrome (PMID: 29330128). ClinVar contains an entry for this variant (Variation ID: 67077). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNQ1 function (PMID: 29330128, 30571187). 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
(Feb 10, 2014)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280153.1
First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Val162Met Based on the information reviewed below, we classify it as a variant of uncertain significance. This variant has previously been reported by Dr. Michael Ackerman’s group and Familion laboratory in one individual tested for LQTS (Kapplinger et al. 2009). There is no published segregation data. Of note in considering cases reported by Kapplinger et al. is the lack of phenotype data on this cohort; we cannot be sure that this individual actually had LQTS. The low yield of 36% in this cohort (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen alongside another variant (9% of the cohort had multiple variants), introduces further uncertainty. It is not entirely possible to tell from the location within the KCNQ1 protein if a variant may cause disease, but there are some clues. When Kapa et al. (2009) compared 388 “clinically definite” LQTS probands to ~1300 healthy controls, they found that while controls do have variants in all regions of the protein, LQTS cases were much more likely to have missense variants in the C-terminal cytoplasmic region of the KCNQ1 protein (amino acid residues 349-676) or the pore/transmembrane/linker region (residues 122-348)—rather than in the N-terminal domain (residues 1-121). Residue 162 falls in the helical S2 transmembrane domain of the transmembrane/linker/pore region, a region in which missense variants are 24x more frequent in LQTS cases than in controls (Kapa et al. 2009). This is a conservative amino acid change, resulting in the replacement of a nonpolar Valine with a nonpolar Methionine. Valine at this location is fairly well conserved across vertebrates, but in some it is replaced by another nonpolar amino acid (including Isoleucine, Glycine, Proline, Alanine). Methionine is not the default amino acid in any of the 90 species reviewed. This Valine residue is also not highly conserved across paralog channel proteins, although Methionine is not one of the alternative amino acids seen (https://cardiodb.org/Paralogue_Annotation/residue.php?gene=KCNQ1&position=162) Variation at nearby residues has been reported in association with LQTS, which supports the functional importance of this region of the protein: Thr153Met, Phe157Cys, Glu160Lys, Glu160Val, Gly168Arg, Thr169Arg, Glu170Gly, Val172Met (GeneDx report; HGMD professional version as of January 17, 2014). In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” with a score of 0.999. The variant is not present in ClinVar. In total the variant has been seen in 2 out of over 60,000 published controls and individuals from publicly available population datasets. The variant was not observed in 1300 published controls, 47% of them Caucasian (Kapplinger et al. 2009). There is no variation at this residue listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is no variation at this residue in 1000 Genomes (http://browser.1000genomes.org/index.htm). The variant is present in 2/32,738 Caucasian individuals in the ExAC dataset, which currently includes variant calls on ~60,000 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian). These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases. (less)
Number of individuals with the variant: 2
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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: SCV000089202.3
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:19716085). 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:19716085). 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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High-Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance. | Vanoye CG | Circulation. Genomic and precision medicine | 2018 | PMID: 30571187 |
Exploiting ion channel structure to assess rare variant pathogenicity. | Kroncke BM | Heart rhythm | 2018 | PMID: 29330128 |
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 |
Text-mined citations for rs199472692 ...
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.