ClinVar Genomic variation as it relates to human health
NM_172107.4(KCNQ2):c.587C>T (p.Ala196Val)
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_172107.4(KCNQ2):c.587C>T (p.Ala196Val)
Variation ID: 21792 Accession: VCV000021792.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20q13.33 20: 63444762 (GRCh38) [ NCBI UCSC ] 20: 62076115 (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 Jan 19, 2017 Oct 20, 2024 Jun 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_172107.4:c.587C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_742105.1:p.Ala196Val missense NM_004518.6:c.587C>T NP_004509.2:p.Ala196Val missense NM_172106.3:c.587C>T NP_742104.1:p.Ala196Val missense NM_172108.5:c.587C>T NP_742106.1:p.Ala196Val missense NM_172109.3:c.587C>T NP_742107.1:p.Ala196Val missense NC_000020.11:g.63444762G>A NC_000020.10:g.62076115G>A NG_009004.2:g.32879C>T - Protein change
- A196V
- Other names
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- Canonical SPDI
- NC_000020.11:63444761: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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Mild decrease in peak current; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0085]Normal rate of activation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0011]Severe depolarizing shift of voltage dependence of activation; Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0026]
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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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- Links
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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KCNQ2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
2153 | 2284 |
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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- | RCV000678083.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 27, 2023 | RCV001066784.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 16, 2021 | RCV001030036.7 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jun 27, 2023 | RCV001092637.31 | |
not provided (1) |
no classification provided
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- | RCV003315300.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 22, 2023 | RCV004528127.1 |
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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Pathogenic
(Jun 27, 2023)
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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: SCV004036384.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect on channel function … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect on channel function (Soldovieri et al., 2007); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25880994, 24375629, 11690625, 32411386, 34489640, 23360469, 23708187, 16686649, 28717674, 27888506, 17475800) (less)
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Pathogenic
(Jan 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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KCNQ2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004111964.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The KCNQ2 c.587C>T variant is predicted to result in the amino acid substitution p.Ala196Val. This variant has been reported in multiple individuals with KCNQ2 related … (more)
The KCNQ2 c.587C>T variant is predicted to result in the amino acid substitution p.Ala196Val. This variant has been reported in multiple individuals with KCNQ2 related disorders (Zara et al. 2013. PubMed ID: 23360469; Carvill et al. 2013. PubMed ID: 23708187; Bennett et al. 2017. PubMed ID: 28717674). It has been documented as a de novo finding, and functional studies support its pathogenicity (Soldovieri et al. 2007. PubMed ID: 17475800; Wang et al. 2020. PubMed ID: 32411386; Jiang et al. 2021. PubMed ID: 34489640). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
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Pathogenic
(May 10, 2019)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 7
Affected status: yes
Allele origin:
de novo
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Center for Molecular Medicine, Children’s Hospital of Fudan University
Accession: SCV001190554.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
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Pathogenic
(Sep 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 7
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001911527.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
Clinical Features:
Delayed speech and language development (present) , Seizure (present) , Cognitive impairment (present)
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Pathogenic
(Mar 08, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004225338.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1, PP3, PM2, PM6, PS3, PS4_moderate
Number of individuals with the variant: 1
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Pathogenic
(Jun 07, 2019)
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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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Revvity Omics, Revvity
Accession: SCV002023231.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jun 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Early infantile epileptic encephalopathy with suppression bursts
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001231804.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individual(s) with benign familial neonatal seizures and early onset epileptic encephalopathy (PMID: 17475800, 23360469, 23708187). In at least … (more)
This missense change has been observed in individual(s) with benign familial neonatal seizures and early onset epileptic encephalopathy (PMID: 17475800, 23360469, 23708187). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 196 of the KCNQ2 protein (p.Ala196Val). ClinVar contains an entry for this variant (Variation ID: 21792). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 17475800). 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 KCNQ2 protein function. (less)
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Pathogenic
(Mar 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249242.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 3
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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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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931984.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 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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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740336.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Seizures, benign familial neonatal, 1
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000041644.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022
Comment:
Functional effect: Rightward shift in current voltage-dependence; decrease in current activation kinetics; novel prepulse-dependence of current activation kinetics
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Comment:
BFNE (benign familial neonatal epilepsy), Rolandic Seizures, Infantile spams.
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not provided
(-)
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no classification provided
Method: literature only
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Complex neurodevelopmental disorder
Affected status: not applicable
Allele origin:
not applicable
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Channelopathy-Associated Epilepsy Research Center
Accession: SCV004015058.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Method: whole-cell patch-clamp recording
Result:
Mild decrease in peak current;Normal rate of activation;Severe depolarizing shift of voltage dependence of activation
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Mild decrease in peak current
Normal rate of activation
Severe depolarizing shift of voltage dependence of activation
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Channelopathy-Associated Epilepsy Research Center
Accession: SCV004015058.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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High-throughput evaluation of epilepsy-associated KCNQ2 variants reveals functional and pharmacological heterogeneity. | Vanoye CG | JCI insight | 2022 | PMID: 35104249 |
KCNQ2-Related Disorders. | Adam MP | - | 2022 | PMID: 20437616 |
Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. | Carvill GL | Nature genetics | 2013 | PMID: 23708187 |
Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance. | Zara F | Epilepsia | 2013 | PMID: 23360469 |
Atypical gating of M-type potassium channels conferred by mutations in uncharged residues in the S4 region of KCNQ2 causing benign familial neonatal convulsions. | Soldovieri MV | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2007 | PMID: 17475800 |
Text-mined citations for rs118192199 ...
HelpRecord last updated Nov 25, 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.