ClinVar Genomic variation as it relates to human health
NM_172107.4(KCNQ2):c.916G>A (p.Ala306Thr)
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.916G>A (p.Ala306Thr)
Variation ID: 7382 Accession: VCV000007382.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20q13.33 20: 63439609 (GRCh38) [ NCBI UCSC ] 20: 62070962 (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 May 1, 2024 Dec 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_172107.4:c.916G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_742105.1:p.Ala306Thr missense NM_004518.6:c.916G>A NP_004509.2:p.Ala306Thr missense NM_172106.3:c.916G>A NP_742104.1:p.Ala306Thr missense NM_172108.5:c.916G>A NP_742106.1:p.Ala306Thr missense NM_172109.3:c.916G>A NP_742107.1:p.Ala306Thr missense NC_000020.11:g.63439609C>T NC_000020.10:g.62070962C>T NG_009004.2:g.38032G>A O43526:p.Ala306Thr - Protein change
- A306T
- Other names
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- Canonical SPDI
- NC_000020.11:63439608:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Mild slowing of activation Functional Epilepsy Nomenclature for Ion Channels [FENICS-0013]
- Severe decrease in peak current Functional Epilepsy Nomenclature for Ion Channels [FENICS-0087]
- 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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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
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. |
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KCNQ2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
2141 | 2272 |
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. |
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Pathogenic (2) |
no assertion criteria provided
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Jan 1, 1998 | RCV000007807.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 1, 2023 | RCV001245227.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 15, 2022 | RCV001564572.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 25, 2019 | RCV002316186.9 | |
not provided (1) |
no classification provided
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- | RCV003315291.8 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV002264637.9 |
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. |
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Pathogenic
(Apr 15, 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: SCV001787757.3
First in ClinVar: Aug 19, 2021 Last updated: Mar 04, 2023 |
Comment:
Reported in a family with benign familial neonatal seizures (Singh et al., 1998); Published functional studies demonstrate altered excitability of the M-type K+ channel, reduction … (more)
Reported in a family with benign familial neonatal seizures (Singh et al., 1998); Published functional studies demonstrate altered excitability of the M-type K+ channel, reduction of seizure threshold, and altered susceptibility to kindling-acquisition in a mouse model (Otto et al., 2009); The majority of missense variants in this gene are considered pathogenic (HGMD); This substitution is predicted to be within the transmembrane segment S6; Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26138355, 19453707, 9425895, 28717674, 24586341) (less)
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Pathogenic
(Dec 01, 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: SCV001418500.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 306 of the KCNQ2 protein (p.Ala306Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 306 of the KCNQ2 protein (p.Ala306Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with benign familial neonatal seizures (PMID: 9425895, 14534157, 24375629). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7382). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 18483067, 19453707). 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: 25959266, 26704558, 27535030). 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
(Nov 25, 2019)
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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: SCV000851351.4
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
The p.A306T pathogenic mutation (also known as c.916G>A), located in coding exon 6 of the KCNQ2 gene, results from a G to A substitution at … (more)
The p.A306T pathogenic mutation (also known as c.916G>A), located in coding exon 6 of the KCNQ2 gene, results from a G to A substitution at nucleotide position 916. The alanine at codon 306 is replaced by threonine, an amino acid with similar properties. This mutation was originally identified in a large family, which showed significant linkage to the KCNQ2 locus on chromosome 20 (Singh NA et al. Nat. Genet., 1998 Jan;18:25-9). Subsequently, this mutation has been reported in patients with neonatal seizures or infantile spasms (Soldovieri MV et al. Hum. Mutat., 2014 Mar;35:356-67; Dimassi S et al. Clin. Genet., 2016 Feb;89:198-204). An in vitro study showed that A306T, located in transmembrane domain S6, reduces potassium currents (Schroeder BC et al. Nature, 1998 Dec;396:687-90). Furthermore, A306T knock-in mice have reduced thresholds to electrically induced seizure and increased sensitivity to chemical convulsant (Singh NA et al. J. Physiol. (Lond.), 2008 Jul;586:3405-23; Otto JF et al. Epilepsia, 2009 Jul;50:1752-9; Tomonoh Y et al. PLoS ONE, 2014 Feb;9:e88549). Based on the available evidence, p.A306T is classified as a pathogenic mutation. (less)
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Pathogenic
(Jan 01, 1998)
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no assertion criteria provided
Method: literature only
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SEIZURES, BENIGN FAMILIAL NEONATAL, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028008.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 20, 2018 |
Comment on evidence:
In kindred 1705, Singh et al. (1998) demonstrated that individuals affected with benign familial neonatal seizures (BFNS1; 121200) had an ala306-to-thr (A306T) amino acid substitution … (more)
In kindred 1705, Singh et al. (1998) demonstrated that individuals affected with benign familial neonatal seizures (BFNS1; 121200) had an ala306-to-thr (A306T) amino acid substitution in the S6 transmembrane segment. This alanine residue was conserved in all members of the Shaker, Shab, Shaw, and Shal subfamilies of potassium channels. (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
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV002546233.1
First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022 |
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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: SCV004015102.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Method: whole-cell patch-clamp recording
Result:
Severe decrease in peak current;Mild slowing of activation;Severe depolarizing shift of voltage dependence of activation
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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: SCV000041664.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022
Comment:
Functional effect: Oocytes: Q2wt:Q2mut:Q3, 20-30% reduced current
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Comment:
BFNE (benign familial neonatal epilepsy). 11/69 FS (febrile seizures); GS (generalized seizures) between 1 and 16 years.
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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
Mild slowing of activation
Severe depolarizing shift of voltage dependence of activation
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Channelopathy-Associated Epilepsy Research Center
Accession: SCV004015102.1
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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 |
KCNQ2 related early-onset epileptic encephalopathies in Chinese children. | Fang ZX | Journal of neurology | 2019 | PMID: 31152295 |
Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies. | Oyrer J | Pharmacological reviews | 2018 | PMID: 29263209 |
ExACtly zero or once: A clinically helpful guide to assessing genetic variants in mild epilepsies. | Bennett CA | Neurology. Genetics | 2017 | PMID: 28717674 |
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 |
The kick-in system: a novel rapid knock-in strategy. | Tomonoh Y | PloS one | 2014 | PMID: 24586341 |
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 |
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 |
Mouse models of human KCNQ2 and KCNQ3 mutations for benign familial neonatal convulsions show seizures and neuronal plasticity without synaptic reorganization. | Singh NA | The Journal of physiology | 2008 | PMID: 18483067 |
KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. | Singh NA | Brain : a journal of neurology | 2003 | PMID: 14534157 |
Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. | Schroeder BC | Nature | 1998 | PMID: 9872318 |
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 rs74315390 ...
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.