ClinVar Genomic variation as it relates to human health
NM_172107.4(KCNQ2):c.917C>T (p.Ala306Val)
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.917C>T (p.Ala306Val)
Variation ID: 219235 Accession: VCV000219235.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20q13.33 20: 63439608 (GRCh38) [ NCBI UCSC ] 20: 62070961 (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 23, 2016 Feb 20, 2024 Apr 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_172107.4:c.917C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_742105.1:p.Ala306Val missense NM_004518.6:c.917C>T NP_004509.2:p.Ala306Val missense NM_172106.3:c.917C>T NP_742104.1:p.Ala306Val missense NM_172108.5:c.917C>T NP_742106.1:p.Ala306Val missense NM_172109.3:c.917C>T NP_742107.1:p.Ala306Val missense NC_000020.11:g.63439608G>A NC_000020.10:g.62070961G>A NG_009004.2:g.38033C>T - Protein change
- A306V
- Other names
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- Canonical SPDI
- NC_000020.11:63439607:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Normal voltage dependence of activation Functional Epilepsy Nomenclature for Ion Channels [FENICS-0032]
- Severe decrease in peak current Functional Epilepsy Nomenclature for Ion Channels [FENICS-0087]
- Severe slowing of activation Functional Epilepsy Nomenclature for Ion Channels [FENICS-0015]
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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 |
2095 | 2214 |
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 (3) |
criteria provided, single submitter
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- | RCV000203598.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 15, 2023 | RCV000545675.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763451.3 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 22, 2022 | RCV001529826.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 29, 2022 | RCV002298526.1 | |
not provided (1) |
no classification provided
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- | RCV003315333.1 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV002510569.2 |
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
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
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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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Pathogenic
(Apr 15, 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: SCV000634081.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala306 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.Ala306 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9425895, 19453707, 26138355). 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: 219235). This missense change has been observed in individual(s) with early onset epileptic encephalopathy and Ohtahara syndrome (PMID: 25959266, 26704558, 27535030, 29390993). 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 306 of the KCNQ2 protein (p.Ala306Val). (less)
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Seizures, benign familial neonatal, 1
Developmental and epileptic encephalopathy, 7
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894227.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Sep 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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KCNQ2-Related Disorders
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002599028.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
Variant summary: KCNQ2 c.917C>T (p.Ala306Val) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five … (more)
Variant summary: KCNQ2 c.917C>T (p.Ala306Val) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250792 control chromosomes. c.917C>T has been reported in the literature in individuals affected with early onset epileptic encephalopathy and Ohtahara syndrome, and in multiple cases was reported as a de novo variant (Ko_2018, Kothur_2018, Fernandez-Marmiesse_2018, Sun_2021, Shellhaas_2017, Bagnall_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants affecting codon 306 have been reported in association with Epilepsy and/or neurodevelopmental disorders in HGMD (A306P, A306T). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive congenital ichthyosis 10
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002820112.1
First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023 |
Comment:
The missense variant p.S53W in PNPLA1 (NM_001145717.1) has been previously reported in homozygous state in an affected patient. The patient had a collodion membrane at … (more)
The missense variant p.S53W in PNPLA1 (NM_001145717.1) has been previously reported in homozygous state in an affected patient. The patient had a collodion membrane at birth (Boyden LM et al).The variant has been submitted to ClinVar as Pathogenic based on the same. The p.S53W variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a large physicochemical difference between serine and tryptophan, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Seizure (present) , Global developmental delay (present) , Abnormal visual fixation (present) , Generalized ichthyosis (present) , Aspiration (present) , Congenital nonbullous ichthyosiform erythroderma (present)
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Pathogenic
(Aug 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV003802793.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
Comment:
The KCNQ2 c.917C>T (p.Ala306Val) missense variant results in the substitution of alanine at amino acid position 306 with valine. This variant has been reported in … (more)
The KCNQ2 c.917C>T (p.Ala306Val) missense variant results in the substitution of alanine at amino acid position 306 with valine. This variant has been reported in at least seven individuals with an early onset epilepsy phenotype, including in one case also associated with sudden unexpected death (PMID: 29390993; PMID: 32139178; PMID: 29455050; PMID: 32917465; PMID: 27535030; PMID: 31780880; PMID: 25959266; PMID: 26704558; PMID: 29852413; PMID: 34120799; PMID: 34055682). In four of these individuals the variant was reported to have occurred de novo (PMID: 34120799; PMID: 29852413; PMID: 27535030; PMID: 29390993). Another variant at the same amino acid position, c.916G>A p.Ala306Thr, has been reported in a heterozygous state in three probands, two with benign familial neonatal convulsions, both individuals inheriting the variant from affected parents (PMID: 9425895; PMID: 24375629). In the third proband the p.Ala306Thr variant was reported to have occurred de novo in a male child with infantile spasm, developmental delay and hypotonia but without epileptic seizures (PMID: 26138355). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. Based on the available evidence, the c.917C>T (p.Ala306Val) variant is classified as pathogenic for KCNQ2-related disorders. (less)
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Pathogenic
(Sep 22, 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: SCV001812203.3
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023 |
Comment:
This substitution is predicted to be within the transmembrane segment S6; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports … (more)
This substitution is predicted to be within the transmembrane segment S6; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 27535030, 23708187, 32139178, 34120799, 29390993, 26704558, 25959266, 29455050, 31780880, 34055682, 29852413) (less)
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Pathogenic
(-)
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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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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004100560.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
The missense variant p.A306V in KCNQ2 (NM_172107.4) has been reported in multiple individuals with Otahara syndrome, wherein it was proved to be de novo in … (more)
The missense variant p.A306V in KCNQ2 (NM_172107.4) has been reported in multiple individuals with Otahara syndrome, wherein it was proved to be de novo in some patients(Rim JH et al,Hortigüela M et al). The variant has been submitted to ClinVar as Pathogenic.The p.A306V variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.A306V missense variant is predicted to be damaging by both SIFT and PolyPhen2. The alanine residue at codon 306 of KCNQ2 is conserved in all mammalian species. The nucleotide c.917 in KCNQ2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Seizure (present) , Global developmental delay (present) , Abnormal visual fixation (present) , Generalized ichthyosis (present) , Aspiration (present) , Increased renal tubular phosphate reabsorption … (more)
Seizure (present) , Global developmental delay (present) , Abnormal visual fixation (present) , Generalized ichthyosis (present) , Aspiration (present) , Increased renal tubular phosphate reabsorption (present) , Congenital nonbullous ichthyosiform erythroderma (present) , Hypotonia (present) (less)
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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: SCV000258968.1
First in ClinVar: Jan 23, 2016 Last updated: Jan 23, 2016 |
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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: SCV001743961.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 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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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926778.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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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: SCV000484595.2
First in ClinVar: Dec 17, 2016 Last updated: Oct 01, 2022 |
Comment:
EE (epileptic encephalopathy)
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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: SCV004015105.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Method: whole-cell patch-clamp recording
Result:
Severe decrease in peak current;Severe slowing of activation;Normal 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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Severe decrease in peak current
Severe slowing of activation
Normal voltage dependence of activation
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Channelopathy-Associated Epilepsy Research Center
Accession: SCV004015105.1
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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 |
Next generation sequencing in children with unexplained epilepsy: A retrospective cohort study. | Chen W | Brain & development | 2021 | PMID: 34120799 |
Detection of Disease-Causing SNVs/Indels and CNVs in Single Test Based on Whole Exome Sequencing: A Retrospective Case Study in Epileptic Encephalopathies. | Sun D | Frontiers in pediatrics | 2021 | PMID: 34055682 |
Clinical characteristics of KCNQ2 encephalopathy. | Kim HJ | Brain & development | 2021 | PMID: 32917465 |
Targeted gene panel sequencing in early infantile onset developmental and epileptic encephalopathy. | Na JH | Brain & development | 2020 | PMID: 32139178 |
Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients. | Fernández-Marmiesse A | Frontiers in neuroscience | 2019 | PMID: 31780880 |
Diagnostic yield of targeted massively parallel sequencing in children with epileptic encephalopathy. | Kothur K | Seizure | 2018 | PMID: 29852413 |
Targeted gene panel and genotype-phenotype correlation in children with developmental and epileptic encephalopathy. | Ko A | Epilepsy research | 2018 | PMID: 29455050 |
Efficient strategy for the molecular diagnosis of intractable early-onset epilepsy using targeted gene sequencing. | Rim JH | BMC medical genomics | 2018 | PMID: 29390993 |
Profile of neonatal epilepsies: Characteristics of a prospective US cohort. | Shellhaas RA | Neurology | 2017 | PMID: 28733343 |
Clinical and genetic features of 13 Spanish patients with KCNQ2 mutations. | Hortigüela M | Journal of human genetics | 2017 | PMID: 27535030 |
Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy. | Bagnall RD | Annals of neurology | 2016 | PMID: 26704558 |
Whole-exome sequencing improves the diagnosis yield in sporadic infantile spasm syndrome. | Dimassi S | Clinical genetics | 2016 | PMID: 26138355 |
Variable clinical expression in patients with mosaicism for KCNQ2 mutations. | Milh M | American journal of medical genetics. Part A | 2015 | PMID: 25959266 |
Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A. | Soldovieri MV | Human mutation | 2014 | PMID: 24375629 |
Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. | Carvill GL | Nature genetics | 2013 | PMID: 23708187 |
Electroconvulsive seizure thresholds and kindling acquisition rates are altered in mouse models of human KCNQ2 and KCNQ3 mutations for benign familial neonatal convulsions. | Otto JF | Epilepsia | 2009 | PMID: 19453707 |
A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. | Singh NA | Nature genetics | 1998 | PMID: 9425895 |
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Text-mined citations for rs864321707 ...
HelpRecord last updated May 12, 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.