ClinVar Genomic variation as it relates to human health
NM_172107.4(KCNQ2):c.794C>T (p.Ala265Val)
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.794C>T (p.Ala265Val)
Variation ID: 120176 Accession: VCV000120176.48
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20q13.33 20: 63442428 (GRCh38) [ NCBI UCSC ] 20: 62073781 (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 May 12, 2024 Jan 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_172107.4:c.794C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_742105.1:p.Ala265Val missense NM_004518.6:c.794C>T NP_004509.2:p.Ala265Val missense NM_172106.3:c.794C>T NP_742104.1:p.Ala265Val missense NM_172108.5:c.794C>T NP_742106.1:p.Ala265Val missense NM_172109.3:c.794C>T NP_742107.1:p.Ala265Val missense NC_000020.11:g.63442428G>A NC_000020.10:g.62073781G>A NG_009004.2:g.35213C>T - Protein change
- A265V
- Other names
- p.A265V:GCG>GTG
- KCNQ2
- Canonical SPDI
- NC_000020.11:63442427: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.
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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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KCNQ2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
2097 | 2217 |
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/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2021 | RCV000106299.22 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 9, 2022 | RCV000187868.33 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 11, 2021 | RCV000768250.10 | |
Pathogenic (1) |
no assertion criteria provided
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Jun 27, 2017 | RCV000578260.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 25, 2023 | RCV001056302.13 | |
Pathogenic (1) |
no assertion criteria provided
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Dec 1, 2017 | RCV001089803.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 1, 2017 | RCV002316289.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 26, 2024 | RCV004546432.1 |
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
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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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Likely pathogenic
(Apr 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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Early infantile epileptic encephalopathy 7
Affected status: yes
Allele origin:
unknown
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000930365.1
First in ClinVar: Aug 04, 2019 Last updated: Aug 04, 2019 |
Geographic origin: Iran
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Pathogenic
(Mar 09, 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: SCV000241468.14
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious … (more)
The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22926866, 23621294, 28867141, 30185235, 31036916, 31418850, 32362866, 32139178, 32917465, 33098118, 32712949, 31785789, 27602407) (less)
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Pathogenic
(Oct 01, 2021)
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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:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002498638.2
First in ClinVar: Apr 11, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change in KCNQ2 is predicted to replace alanine with valine at codon 265 (p.(Ala265Val)). The alanine residue is highly conserved (100 vertebrates, UCSC), … (more)
This sequence change in KCNQ2 is predicted to replace alanine with valine at codon 265 (p.(Ala265Val)). The alanine residue is highly conserved (100 vertebrates, UCSC), and is located in the transmembrane ion transport domain in a region, amino acids 1-369, that is highly constrained. There is a moderate physicochemical difference between alanine and valine. This variant is absent from gnomAD v2.1 and v3.1. This variant has been identified as a de novo occurrence with confirmed parental relationships in 3 individuals and as a de novo occurrence with unconfirmed parental relationships in 2 individuals with Ohtahara syndrome or undetermined neonatal epileptic encephalopathy (NEE; PMID: 22926866, 23621294, 25959266, 32362866, 34354098). It has also been identified in 2 individuals with NEE and unknown de novo status (PMID: 25959266, 34395220). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict deleterious). Another missense variant c.793G>A, p.Ala265Thr in the same codon has been classified as pathogenic for NEE (ClinVar Variation ID: 197891). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PS2/PM6_Strong, PM1, PM5, PS4_Supporting, PM2_Supporting. (less)
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Likely pathogenic
(May 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000850924.4
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
The p.A265V variant (also known as c.794C>T), located in coding exon 5 of the KCNQ2 gene, results from a C to T substitution at nucleotide … (more)
The p.A265V variant (also known as c.794C>T), located in coding exon 5 of the KCNQ2 gene, results from a C to T substitution at nucleotide position 794. The alanine at codon 265 is replaced by valine, an amino acid with similar properties. This variant as been observed de novo in unrelated patients with early onset epileptic encephalopathy (Saitsu H et al. Ann. Neurol., 2012 Aug;72:298-300; Milh M et al. Am. J. Med. Genet. A, 2015 Oct;167A:2314-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Aug 01, 2020)
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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: SCV000575317.27
First in ClinVar: Oct 09, 2016 Last updated: May 12, 2024 |
Number of individuals with the variant: 2
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Pathogenic
(Jun 26, 2017)
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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:
unknown
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Study: Clinvar_gadteam_Clinical_exome_analysis_3
Accession: SCV000803835.1 First in ClinVar: Jun 02, 2018 Last updated: Jun 02, 2018 |
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Likely pathogenic
(Nov 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 7
Seizures, benign familial neonatal, 1
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV000898776.2
First in ClinVar: Apr 25, 2019 Last updated: May 06, 2023 |
Comment:
KCNQ2 NM_172107 exon 5 p.Ala265Val (c.794C>T): This variant has been reported in the literature in at least 2 individuals (1 with early onset epileptic encephalopathy … (more)
KCNQ2 NM_172107 exon 5 p.Ala265Val (c.794C>T): This variant has been reported in the literature in at least 2 individuals (1 with early onset epileptic encephalopathy and 1 with Ohtahara syndrome), both of whom were reported as de novo (Saitsu 2012 PMID:2292866, Kato 2013 PMID:23621294). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:120176). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, other variants at this position (p.Ala265Thr, p.Ala265Pro) have been reported in association with disease, suggesting that this codon has functional significance. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic. (less)
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Pathogenic
(Jun 25, 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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Invitae
Accession: SCV001220740.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala265 amino acid residue in KCNQ2. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. 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, 23692823, 27535030, 27602407, 27779742). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 120176). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 22926866, 30185235). In at least one individual the variant was observed to be de novo. 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 265 of the KCNQ2 protein (p.Ala265Val). (less)
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Pathogenic
(Jan 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Seizures
Affected status: yes
Allele origin:
de novo
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV005040959.1
First in ClinVar: May 12, 2024 Last updated: May 12, 2024 |
Sex: female
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Pathogenic
(Jun 27, 2017)
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no assertion criteria provided
Method: clinical testing
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KCNQ2-related disorders
Affected status: yes
Allele origin:
de novo
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Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV000680117.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
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Pathogenic
(Dec 01, 2017)
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no assertion criteria provided
Method: clinical testing
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Intellectual disability
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Diagnostic Laboratory, Strasbourg University Hospital
Accession: SCV001244215.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
Age: 0-9 years
Sex: female
Method: targeted capture
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Pathogenic
(Jul 01, 2013)
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no assertion criteria provided
Method: literature only
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DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 7
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000143758.4
First in ClinVar: Mar 24, 2014 Last updated: Oct 23, 2020 |
Comment on evidence:
In a 3-month-old Japanese boy with developmental and epileptic encephalopathy (DEE7; 613720), Saitsu et al. (2012) identified a de novo heterozygous c.794C-T transition in the … (more)
In a 3-month-old Japanese boy with developmental and epileptic encephalopathy (DEE7; 613720), Saitsu et al. (2012) identified a de novo heterozygous c.794C-T transition in the KCNQ2 gene, resulting in an ala265-to-val (A265V) substitution. The patient developed tonic spasms on the first day of life and then had intractable seizures associated with a suppression-burst pattern on EEG; he was diagnosed clinically with Ohtahara syndrome. He had delayed development and no eye pursuit. The patient was 1 of 12 probands with a similar disorder who underwent whole-exome sequencing. Functional studies were not performed. Kato et al. (2013) identified a de novo heterozygous A265V substitution in 2 unrelated Japanese patients with DEE7. The mutations, which were found by whole-exome sequencing, were not present in 212 control exomes. Onset of seizures in both patients occurred in the early neonatal period. (less)
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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: SCV000484579.2
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 |
Genetic Diagnosis in Children with Epilepsy and Developmental Disorders by Targeted Gene Panel Analysis in a Developing Country. | Rahman MM | Journal of epilepsy research | 2021 | PMID: 34395220 |
The relationship between the characteristics of burst suppression pattern and different etiologies in epilepsy. | Yang H | Scientific reports | 2021 | PMID: 34354098 |
KCNQ2-Neonatal Epileptic Encephalopathy Complicated by Ventricular Tachycardia: A Case Report. | Geng Y | Frontiers in neurology | 2020 | PMID: 32362866 |
Novel and de novo mutations in pediatric refractory epilepsy. | Liu J | Molecular brain | 2018 | PMID: 30185235 |
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 |
Variable clinical expression in patients with mosaicism for KCNQ2 mutations. | Milh M | American journal of medical genetics. Part A | 2015 | PMID: 25959266 |
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 |
Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation. | Kato M | Epilepsia | 2013 | PMID: 23621294 |
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 |
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Text-mined citations for rs587777219 ...
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.