ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.928G>A (p.Val310Ile)
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
-
NM_000218.3(KCNQ1):c.928G>A (p.Val310Ile)
Variation ID: 53133 Accession: VCV000053133.8
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p15.5 11: 2583441 (GRCh38) [ NCBI UCSC ] 11: 2604671 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Sep 20, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000218.3:c.928G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Val310Ile missense NM_001406836.1:c.928G>A NP_001393765.1:p.Val310Ile missense NM_001406837.1:c.658G>A NP_001393766.1:p.Val220Ile missense NM_001406838.1:c.484G>A NP_001393767.1:p.Val162Ile missense NM_181798.2:c.547G>A NP_861463.1:p.Val183Ile missense NR_040711.2:n.821G>A NC_000011.10:g.2583441G>A NC_000011.9:g.2604671G>A NG_008935.1:g.143451G>A LRG_287:g.143451G>A LRG_287t1:c.928G>A LRG_287p1:p.Val310Ile LRG_287t2:c.547G>A LRG_287p2:p.Val183Ile P51787:p.Val310Ile - Protein change
- V310I, V183I, V162I, V220I
- Other names
- -
- Canonical SPDI
- NC_000011.10:2583440:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
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 | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
KCNQ1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
1703 | 2599 |
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. |
---|---|---|---|---|
not provided (1) |
no classification provided
|
- | RCV000057804.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 28, 2017 | RCV000520168.2 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 16, 2023 | RCV001852980.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 20, 2023 | RCV003591650.1 |
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
Help
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Sep 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac arrhythmia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004358396.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces valine with isoleucine at codon 310 in the KCNQ1 protein. This variant is found within the highly conserved pore-forming domain (a.a. … (more)
This missense variant replaces valine with isoleucine at codon 310 in the KCNQ1 protein. This variant is found within the highly conserved pore-forming domain (a.a. 300-320). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267) Functional studies have shown that this variant moderately affects channel trafficking by retention of the mutant protein in the endoplasmic reticulum (PMID: 24912595) and causes a reduction in potassium channel current (PMID: 15051636, 15649981). This variant has been reported in several individuals affected long QT syndrome (PMID: 10973849, 15051636 , 17470695, 19490272, 24912595, 26318259). In two of these individuals, this variant was observed in compound heterozygous state with a known pathogenic KCNQ1 variant (PMID: 15051636 , 24912595). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
|
|
Likely pathogenic
(Jul 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000617071.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
The V310I likely pathogenic variant in the KCNQ1 gene has been reported in several individuals with LQTS (Splawski et al., 2000; Moss et al., 2007), … (more)
The V310I likely pathogenic variant in the KCNQ1 gene has been reported in several individuals with LQTS (Splawski et al., 2000; Moss et al., 2007), though detailed clinical and segregation information were not provided. Additionally, this variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Though the V310I variant is a conservative amino acid substitution, it occurs at a position that is conserved across species, and in silico analysis suggests that this variant is probably damaging to the protein structure/function. Furthermore, functional studies show that the V310I pathogenic variant results in partial loss of potassium channel function (Westenskow et al., 2004; Seebohm et al., 2005). Finally, multiple missense variants in nearby residues (W305S, W305L, G306R, V307M, T312I, G314S, Y315C, Y315S) are independently classified as likely pathogenic/pathogenic by GeneDx. (less)
|
|
Likely pathogenic
(Nov 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002180989.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 15051636, 15649981, 24912595). 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. ClinVar contains an entry for this variant (Variation ID: 53133). This missense change has been observed in individuals with long QT syndrome (PMID: 15051636, 19490272). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 310 of the KCNQ1 protein (p.Val310Ile). (less)
|
|
Likely Pathogenic
(Aug 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004830334.1
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)
|
Comment:
This variant has been reported in multiple individuals with Long QT syndrome (PMID: 10973849, 17470695, 19490272, 26318259, 29033053, 27041150, 31565860). This variant is located in … (more)
This variant has been reported in multiple individuals with Long QT syndrome (PMID: 10973849, 17470695, 19490272, 26318259, 29033053, 27041150, 31565860). This variant is located in a well-established functional domain of the protein where other pathogenic or likely pathogenic variants have been described (PMID: 32893267). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to be deleterious by in silico analysis. Functional studies suggest that this variant results in a deleterious effect on the protein (PMID: 32893267, 15649981). (less)
Number of individuals with the variant: 2
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089324.3
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:10973849;PMID:15051636;PMID:17470695;PMID:15649981). 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:10973849;PMID:15051636;PMID:17470695;PMID:15649981). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)
|
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 |
---|---|---|---|---|
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 |
Compound and heterozygous mutations of KCNQ1 in long QT syndrome with familial history of unexplained sudden death: Identified by analysis of whole exome sequencing and predisposing genes. | Lin Y | Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc | 2020 | PMID: 31565860 |
Identification and characterization of a novel recessive KCNQ1 mutation associated with Romano-Ward Long-QT syndrome in two Iranian families. | Zafari Z | Journal of electrocardiology | 2017 | PMID: 29033053 |
KCNQ1 mutations associated with Jervell and Lange-Nielsen syndrome and autosomal recessive Romano-Ward syndrome in India-expanding the spectrum of long QT syndrome type 1. | Vyas B | American journal of medical genetics. Part A | 2016 | PMID: 27041150 |
Stop-codon and C-terminal nonsense mutations are associated with a lower risk of cardiac events in patients with long QT syndrome type 1. | Ruwald MH | Heart rhythm | 2016 | PMID: 26318259 |
Cellular mechanisms underlying the increased disease severity seen for patients with long QT syndrome caused by compound mutations in KCNQ1. | Harmer SC | The Biochemical journal | 2014 | PMID: 24912595 |
Mutations in conserved amino acids in the KCNQ1 channel and risk of cardiac events in type-1 long-QT syndrome. | Jons C | Journal of cardiovascular electrophysiology | 2009 | PMID: 19490272 |
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 |
Mutation of colocalized residues of the pore helix and transmembrane segments S5 and S6 disrupt deactivation and modify inactivation of KCNQ1 K+ channels. | Seebohm G | The Journal of physiology | 2005 | PMID: 15649981 |
Compound mutations: a common cause of severe long-QT syndrome. | Westenskow P | Circulation | 2004 | PMID: 15051636 |
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. | Splawski I | Circulation | 2000 | PMID: 10973849 |
click to load more click to collapse |
Text-mined citations for rs199472745 ...
HelpRecord last updated May 08, 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.