ClinVar Genomic variation as it relates to human health
NM_004974.4(KCNA2):c.1214C>T (p.Pro405Leu)
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_004974.4(KCNA2):c.1214C>T (p.Pro405Leu)
Variation ID: 190325 Accession: VCV000190325.42
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p13.3 1: 110603569 (GRCh38) [ NCBI UCSC ] 1: 111146191 (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 Dec 6, 2016 May 12, 2024 Mar 14, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004974.4:c.1214C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004965.1:p.Pro405Leu missense NM_001204269.2:c.894+320C>T intron variant NC_000001.11:g.110603569G>A NC_000001.10:g.111146191G>A NG_027997.2:g.32906C>T P16389:p.Pro405Leu - Protein change
- P405L
- Other names
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- Canonical SPDI
- NC_000001.11:110603568: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
Help
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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KCNA2 | - | - |
GRCh38 GRCh37 |
458 | 480 |
Conditions - Germline
Condition
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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
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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 (8) |
criteria provided, multiple submitters, no conflicts
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Mar 14, 2024 | RCV000170511.21 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 17, 2021 | RCV000407449.23 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 30, 2021 | RCV002517634.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 27, 2023 | RCV004546448.1 |
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
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
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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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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447211.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Focal-onset seizure (present) , Cerebellar ataxia (present) , Global developmental delay (present) , Spastic hemiparesis (present)
Sex: female
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Likely pathogenic
(Jun 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 32
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001950005.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Nov 17, 2021)
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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: SCV000329995.7
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional study demonstrates loss of channel function through a dominant negative effect (Syrbe et al., 2015); Not observed at significant frequency in large population … (more)
Published functional study demonstrates loss of channel function through a dominant negative effect (Syrbe et al., 2015); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25997620, 30182498, 29050392, 28600779, 28806589, 30055040, 28488083, 29895856, 27864847, 33232902, 33802230, 33355533, 34576077, 31932120, 25751627) (less)
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Pathogenic
(Mar 14, 2024)
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criteria provided, single submitter
Method: research
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Developmental and epileptic encephalopathy, 32
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004801198.2
First in ClinVar: Mar 16, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Aug 09, 2017)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 32
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV001164173.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Pathogenic
(Apr 19, 2018)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 32
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001426145.1
First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020 |
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Pathogenic
(Jan 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 32
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002023206.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 32
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001215242.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 405 of the KCNA2 protein (p.Pro405Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 405 of the KCNA2 protein (p.Pro405Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 25751627). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 190325). 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. 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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Pathogenic
(Jun 30, 2021)
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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: SCV003745333.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.1214C>T (p.P405L) alteration is located in exon 3 (coding exon 1) of the KCNA2 gene. This alteration results from a C to T substitution … (more)
The c.1214C>T (p.P405L) alteration is located in exon 3 (coding exon 1) of the KCNA2 gene. This alteration results from a C to T substitution at nucleotide position 1214, causing the proline (P) at amino acid position 405 to be replaced by a leucine (L). Based on data from the Genome Aggregation Database (gnomAD), the KCNA2 c.1214C>T alteration was not observed, with coverage at this position. This alteration has been reported in multiple unrelated patients with epileptic encephalopathy and is the most common recurrent variant in KCNA2 (Syrbe, 2015; Masnada, 2017; Sachdev, 2017; Miao, 2018; Gong, 2020). This amino acid position is highly conserved in available vertebrate species. Functional characterization of the P405L alteration with a voltage-clamp oocyte testing system found a dramatic reduction of current amplitudes with a dominant negative effect (Syrbe, 2015). The p.P405L alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Sep 01, 2021)
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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: SCV001248404.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 3
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Pathogenic
(Dec 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Seizures
Affected status: yes
Allele origin:
unknown
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV005043046.1
First in ClinVar: May 12, 2024 Last updated: May 12, 2024 |
Sex: male
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Pathogenic
(Jun 07, 2017)
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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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Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV000778262.1
First in ClinVar: Jun 02, 2018 Last updated: Jun 02, 2018 |
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Pathogenic
(Apr 01, 2015)
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no assertion criteria provided
Method: literature only
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DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 32
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000222943.3
First in ClinVar: May 19, 2015 Last updated: Oct 29, 2020 |
Comment on evidence:
In 3 unrelated patients (patients 1, 4, and 5) with developmental and epileptic encephalopathy-32 (DEE32; 616366), Syrbe et al. (2015) identified a de novo heterozygous … (more)
In 3 unrelated patients (patients 1, 4, and 5) with developmental and epileptic encephalopathy-32 (DEE32; 616366), Syrbe et al. (2015) identified a de novo heterozygous c.1214C-T transition (c.1214C-T, NM_004974) in the KCNA2 gene, resulting in a pro405-to-leu (P405L) substitution at a highly conserved residue in the S6 transmembrane pore domain of the channel. The mutation, which was found by whole-exome or next-generation sequencing of a targeted panel of putative epilepsy genes, was not found in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, or Exome Aggregation Consortium databases. In vitro functional expression studies in Xenopus oocytes showed that the P405L mutation caused a dramatic reduction in current amplitude in a dominant-negative manner, consistent with a loss of channel function. After normal early development, the patients had onset of seizures between 8 and 17 months of age. They became seizure-free between 4 and 15 years of age. (less)
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Pathogenic
(Jan 29, 2019)
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no assertion criteria provided
Method: clinical testing
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Developmental and epileptic encephalopathy, 32
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001132802.1
First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020 |
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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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Generation of a human iPSC line from an epileptic encephalopathy patient with electrical status epilepticus during sleep carrying KCNA2 (p.P405L) mutation. | Gong P | Stem cell research | 2020 | PMID: 33232902 |
Genotype and phenotype analysis using an epilepsy-associated gene panel in Chinese pediatric epilepsy patients. | Miao P | Clinical genetics | 2018 | PMID: 30182498 |
Clinical spectrum and genotype-phenotype associations of KCNA2-related encephalopathies. | Masnada S | Brain : a journal of neurology | 2017 | PMID: 29050392 |
Novel clinical manifestations in patients with KCNA2 mutations. | Sachdev M | Seizure | 2017 | PMID: 28806589 |
De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. | Syrbe S | Nature genetics | 2015 | PMID: 25751627 |
Text-mined citations for this variant ...
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.