Functional studies indicate a gain-of-function effect that disrupts normal function of the Kv1.2 potassium channel (Syrbe et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33802230, 31628766, 31692161, 30660924, 27535533, 31075689, 31487502, 31054490, 30283815, 29050392, 27733563, 25751627, 25477152)
ClinVar Genomic variation as it relates to human health
NM_004974.4(KCNA2):c.890G>A (p.Arg297Gln)
Germline
Classification
Help
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.
(11)
Help
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.
Pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004974.4(KCNA2):c.890G>A (p.Arg297Gln)
Variation ID: 190328 Accession: VCV000190328.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p13.3 1: 110603893 (GRCh38) [ NCBI UCSC ] 1: 111146515 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 21, 2017 Oct 20, 2024 Jan 22, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004974.4:c.890G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004965.1:p.Arg297Gln missense NM_001204269.2:c.890G>A NP_001191198.1:p.Arg297Gln missense NM_004974.2:c.890G>A NC_000001.11:g.110603893C>T NC_000001.10:g.111146515C>T NG_027997.2:g.32582G>A P16389:p.Arg297Gln - Protein change
- R297Q
- Other names
- -
- Canonical SPDI
- NC_000001.11:110603892:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| KCNA2 | - | - |
GRCh38 GRCh37 |
472 | 494 | |
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. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 22, 2024 | RCV000170514.20 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 21, 2021 | RCV000264400.26 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 26, 2016 | RCV000622743.3 | |
| Likely pathogenic (2) |
no assertion criteria provided
|
Jan 1, 2019 | RCV001252020.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 18, 2020 | RCV001374910.2 |
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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|---|---|---|---|---|---|
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Pathogenic
(Apr 26, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000740688.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Caucasian
|
|
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Pathogenic
(Jan 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248407.26
First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
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Pathogenic
(Jan 04, 2021)
|
criteria provided, single submitter
Method: research
|
Developmental and epileptic encephalopathy, 32
Affected status: yes
Allele origin:
de novo
|
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris
Accession: SCV001519145.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
|
|
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Pathogenic
(Feb 18, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV001572197.1
First in ClinVar: Apr 28, 2021 Last updated: Apr 28, 2021 |
|
|
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Pathogenic
(Jun 21, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329629.6
First in ClinVar: Dec 06, 2016 Last updated: Apr 17, 2019 |
Comment:
Functional studies indicate a gain-of-function effect that disrupts normal function of the Kv1.2 potassium channel (Syrbe et al., 2015); Not observed in large population cohorts … (more)
Functional studies indicate a gain-of-function effect that disrupts normal function of the Kv1.2 potassium channel (Syrbe et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33802230, 31628766, 31692161, 30660924, 27535533, 31075689, 31487502, 31054490, 30283815, 29050392, 27733563, 25751627, 25477152) (less)
|
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Pathogenic
(Oct 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 32
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV002012165.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novoo in similarly affected unrelated individuals (PMID:25477152, 25751627, … (more)
Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novoo in similarly affected unrelated individuals (PMID:25477152, 25751627, 27733563, PS2, PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Glu545Lys) has been reported as pathogenic (VCV000013655.18 PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.982, 3Cnet: 0.967, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Seizure (present) , Intellectual disability (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Intellectual disability (present) , Cerebellar ataxia … (more)
Seizure (present) , Intellectual disability (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Intellectual disability (present) , Cerebellar ataxia (present) , Delayed speech and language development (present) (less)
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Pathogenic
(Jan 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 32
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000656459.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 297 of the KCNA2 protein (p.Arg297Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 297 of the KCNA2 protein (p.Arg297Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant epileptic encephalopathy (PMID: 25477152, 25751627, 27733563). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 190328). 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 KCNA2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KCNA2 function (PMID: 25751627). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Likely pathogenic
(Jan 01, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Epileptic encephalopathy, early infantile, 1
Affected status: yes
Allele origin:
unknown
|
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV001427767.1
First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020 |
|
|
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Pathogenic
(Apr 01, 2015)
|
no assertion criteria provided
Method: literature only
|
DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 32
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000222946.4
First in ClinVar: May 19, 2015 Last updated: Oct 30, 2020 |
Comment on evidence:
By exome sequencing in a 7-year-old boy who presented in infancy with ataxia and myoclonic epilepsy (DEE32; 616366), Pena and Coimbra (2015) identified a heterozygous … (more)
By exome sequencing in a 7-year-old boy who presented in infancy with ataxia and myoclonic epilepsy (DEE32; 616366), Pena and Coimbra (2015) identified a heterozygous de novo c.890G-A transition in the KCNA2 gene, resulting in an arg297-to-gln (R297Q) substitution at the second of the critical arginines in the S4 helix, which corresponds to the voltage sensor. The mutation, which was confirmed by Sanger sequencing, was not found in the patient's parents or in the Exome Variant Server database. (In the article by Pena and Coimbra (2015), the nucleotide change was given as c.890C-A in the abstract but as c.890G-A in the text and Figure S1.) The patient had myoclonic seizures and ataxia. In a 26-year-old man (patient 7) with DEE32, Syrbe et al. (2015) identified a de novo heterozygous c.890G-A transition (c.890G-A, NM_004974) in the KCNA2 gene, resulting in the R297Q substitution. The mutation was found by whole-exome sequencing of 12 patients with early-onset ataxia and epilepsy. In vitro functional expression studies in Xenopus oocytes showed that the R297Q mutation caused a gain of function, with increased current amplitude and negative shifting of the voltage dependence of activation by -40 mV, resulting in permanent opening of the channel. The effect was dominant on the wildtype protein. The patient presented at 5 months of age with febrile status epilepticus. He had moderate intellectual disability and was ataxic. (less)
|
|
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Pathogenic
(Sep 08, 2002)
|
no assertion criteria provided
Method: research
|
Developmental and epileptic encephalopathy, 32
Affected status: yes
Allele origin:
unknown
|
Center of Excellence for Medical Genomics, Chulalongkorn University
Accession: SCV002570058.1
First in ClinVar: Sep 10, 2022 Last updated: Sep 10, 2022 |
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Developmental and epileptic encephalopathy, 1
Affected status: yes
Allele origin:
unknown
|
GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228662.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Pathogenic and reported on 12-31-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Pathogenic and reported on 12-31-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Phenotypic abnormality (present)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2019-12-31
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novoo in similarly affected unrelated individuals (PMID:25477152, 25751627, 27733563, PS2, PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Glu545Lys) has been reported as pathogenic (VCV000013655.18 PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.982, 3Cnet: 0.967, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 297 of the KCNA2 protein (p.Arg297Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant epileptic encephalopathy (PMID: 25477152, 25751627, 27733563). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 190328). 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 KCNA2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KCNA2 function (PMID: 25751627). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant interpreted as Pathogenic and reported on 12-31-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
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. |
Comment:
Functional studies indicate a gain-of-function effect that disrupts normal function of the Kv1.2 potassium channel (Syrbe et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33802230, 31628766, 31692161, 30660924, 27535533, 31075689, 31487502, 31054490, 30283815, 29050392, 27733563, 25751627, 25477152)
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novoo in similarly affected unrelated individuals (PMID:25477152, 25751627, 27733563, PS2, PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Glu545Lys) has been reported as pathogenic (VCV000013655.18 PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.982, 3Cnet: 0.967, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 297 of the KCNA2 protein (p.Arg297Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant epileptic encephalopathy (PMID: 25477152, 25751627, 27733563). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 190328). 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 KCNA2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KCNA2 function (PMID: 25751627). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant interpreted as Pathogenic and reported on 12-31-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy. | Corbett MA | Neurology | 2016 | PMID: 27733563 |
| De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. | Syrbe S | Nature genetics | 2015 | PMID: 25751627 |
| Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
| Ataxia and myoclonic epilepsy due to a heterozygous new mutation in KCNA2: proposal for a new channelopathy. | Pena SD | Clinical genetics | 2015 | PMID: 25477152 |
| Effect of sensor domain mutations on the properties of voltage-gated ion channels: molecular dynamics studies of the potassium channel Kv1.2. | Delemotte L | Biophysical journal | 2010 | PMID: 21044565 |
| Voltage sensor of Kv1.2: structural basis of electromechanical coupling. | Long SB | Science (New York, N.Y.) | 2005 | PMID: 16002579 |
| Voltage-sensing arginines in a potassium channel permeate and occlude cation-selective pores. | Tombola F | Neuron | 2005 | PMID: 15694325 |
| Contribution of the S4 segment to gating charge in the Shaker K+ channel. | Aggarwal SK | Neuron | 1996 | PMID: 8663993 |
| Voltage-sensing residues in the S2 and S4 segments of the Shaker K+ channel. | Seoh SA | Neuron | 1996 | PMID: 8663992 |
Text-mined citations for rs786205232 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 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.