ClinVar Genomic variation as it relates to human health
NM_172107.4(KCNQ2):c.793G>A (p.Ala265Thr)
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.793G>A (p.Ala265Thr)
Variation ID: 197891 Accession: VCV000197891.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20q13.33 20: 62073782 (GRCh37) [ NCBI UCSC ] 20: 63442429 (GRCh38) [ 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 28, 2015 Oct 8, 2024 Dec 21, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_172107.4:c.793G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_742105.1:p.Ala265Thr missense NM_004518.6:c.793G>A NP_004509.2:p.Ala265Thr missense NM_172106.3:c.793G>A NP_742104.1:p.Ala265Thr missense NM_172107.3:c.793G>A NM_172108.5:c.793G>A NP_742106.1:p.Ala265Thr missense NM_172109.3:c.793G>A NP_742107.1:p.Ala265Thr missense NC_000020.11:g.63442429C>T NC_000020.10:g.62073782C>T NG_009004.2:g.35212G>A - Protein change
- A265T
- Other names
- p.A265T:GCG>ACG
- Canonical SPDI
- NC_000020.11:63442428:C:T
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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
Help
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 |
2143 | 2274 |
Conditions - Germline
Condition
Help
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 (3) |
criteria provided, single submitter
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Dec 21, 2023 | RCV000179032.9 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 23, 2023 | RCV000187875.30 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 3, 2014 | RCV000192955.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 17, 2023 | RCV000555510.10 |
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
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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
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. |
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Likely pathogenic
(Jun 03, 2014)
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criteria provided, single submitter
Method: clinical testing
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Seizures
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000247667.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Likely pathogenic
(Oct 22, 2014)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000231221.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001448017.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Seizure (present) , Global developmental delay (present) , Abnormal muscle tone (present)
Sex: male
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Pathogenic
(Aug 17, 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: SCV000634076.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 265 of the KCNQ2 protein (p.Ala265Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 265 of the KCNQ2 protein (p.Ala265Thr). This variant is present in population databases (rs794727740, gnomAD 0.0009%). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 23692823, 27535030, 27602407, 27779742). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 197891). 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. This variant disrupts the p.Ala265 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22275249, 22926866). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 23, 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: SCV000241475.10
First in ClinVar: Aug 07, 2015 Last updated: Apr 09, 2023 |
Comment:
Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Missense variants in this gene are often considered pathogenic (HGMD); 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: 23692823, 28133863, 28867141, 29056246, 28191890, 24318194, 27779742, 25533962, 28135719, 27535030, 33084218, 31957018, 31785789, 33811133, 31440721, 34992632, 27602407) (less)
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Pathogenic
(Dec 21, 2023)
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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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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV003921969.2
First in ClinVar: May 06, 2023 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with developmental and epileptic encephalopathy 7 (MIM#613720; PMID: 24318194). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Two different variants in the same codon resulting in changes to valine and proline have been previously reported as pathogenic in patients with a KCNQ2-related seizure disorder (ClinVar, PMID: 31552204). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in patients with a KCNQ2-related seizure disorder (ClinVar, PMID: 29056246, PMID: 27535030). (SP) 1102 - Strong phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jul 01, 2018)
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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: SCV001247386.25
First in ClinVar: May 09, 2020 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Developmental and epileptic encephalopathy, 7
Affected status: yes
Allele origin:
de novo
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NeuroMeGen, Hospital Clinico Santiago de Compostela
Accession: SCV000258972.1
First in ClinVar: Jan 22, 2016 Last updated: Jan 22, 2016 |
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not provided
(-)
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no classification provided
Method: literature only
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Developmental and epileptic encephalopathy, 7
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000484577.2
First in ClinVar: Dec 17, 2016 Last updated: Oct 01, 2022 |
Comment:
EE (epileptic encephalopathy)
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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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KCNQ2-Related Disorders. | Adam MP | - | 2022 | PMID: 20437616 |
A de novo KCNQ2 Gene Mutation Associated With Non-familial Early Onset Seizures: Case Report and Revision of Literature Data. | Laccetta G | Frontiers in pediatrics | 2019 | PMID: 31552204 |
Diagnostic Yield From 339 Epilepsy Patients Screened on a Clinical Gene Panel. | Butler KM | Pediatric neurology | 2017 | PMID: 29056246 |
Gene mutation analysis of 175 Chinese patients with early-onset epileptic encephalopathy. | Zhang Q | Clinical genetics | 2017 | PMID: 27779742 |
Clinical and genetic features of 13 Spanish patients with KCNQ2 mutations. | Hortigüela M | Journal of human genetics | 2017 | PMID: 27535030 |
KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients. | Millichap JJ | Neurology. Genetics | 2016 | PMID: 27602407 |
Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. | Orhan G | Annals of neurology | 2014 | PMID: 24318194 |
Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients. | Weckhuysen S | Neurology | 2013 | PMID: 24107868 |
Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2. | Milh M | Orphanet journal of rare diseases | 2013 | PMID: 23692823 |
Whole exome sequencing identifies KCNQ2 mutations in Ohtahara syndrome. | Saitsu H | Annals of neurology | 2012 | PMID: 22926866 |
KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. | Weckhuysen S | Annals of neurology | 2012 | PMID: 22275249 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=KCNQ2 | - | - | - | - |
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Text-mined citations for rs794727740 ...
HelpRecord last updated Oct 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.