ClinVar Genomic variation as it relates to human health
NM_001205293.3(CACNA1E):c.2104G>A (p.Ala702Thr)
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_001205293.3(CACNA1E):c.2104G>A (p.Ala702Thr)
Variation ID: 521483 Accession: VCV000521483.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q25.3 1: 181724499 (GRCh38) [ NCBI UCSC ] 1: 181693635 (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 Apr 15, 2018 Feb 14, 2024 Apr 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001205293.3:c.2104G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001192222.1:p.Ala702Thr missense NM_000721.4:c.2104G>A NP_000712.2:p.Ala702Thr missense NM_001205294.2:c.2104G>A NP_001192223.1:p.Ala702Thr missense NC_000001.11:g.181724499G>A NC_000001.10:g.181693635G>A NG_050616.1:g.246189G>A - Protein change
- A702T
- Other names
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- Canonical SPDI
- NC_000001.11:181724498: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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CACNA1E | - | - |
GRCh38 GRCh37 |
1955 | 1986 |
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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Likely pathogenic (1) |
criteria provided, single submitter
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Mar 7, 2017 | RCV000624563.4 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2023 | RCV000754084.10 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2022 | RCV001269715.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 28, 2021 | RCV001756024.2 | |
Likely pathogenic (1) |
no assertion criteria provided
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Nov 1, 2018 | RCV001849415.2 |
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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Pathogenic
(Feb 06, 2020)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 69
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV001432145.1 First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Upper limb asymmetry (present) , U-Shaped upper lip vermilion (present) , Thin upper lip vermilion (present) , Thick nasal alae (present) , Sparse eyebrow (present) … (more)
Upper limb asymmetry (present) , U-Shaped upper lip vermilion (present) , Thin upper lip vermilion (present) , Thick nasal alae (present) , Sparse eyebrow (present) , Single transverse palmar crease (present) , Short nose (present) , Short foot (present) , Severe muscular hypotonia (present) , Severe global developmental delay (present) , Nuchal cord (present) , Micrognathia (present) , Maternal seizures (present) , Lower limb asymmetry (present) , Hypsarrhythmia (present) , Hypoplastic toenails (present) , Hypoplasia of the primary teeth (present) , High, narrow palate (present) , High forehead (present) , Everted lower lip vermilion (present) , Depressed nasal bridge (present) , Bridged palmar crease (present) , Anteverted nares (present) , Adducted thumb (present) , Abdominal distention (present) (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Hispanic Americans
Tissue: blood and fibroblasts
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2020-02-06
Testing laboratory interpretation: Pathogenic
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Likely pathogenic
(Jun 15, 2018)
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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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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449915.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Oct 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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Van der Woude syndrome 1
Affected status: yes
Allele origin:
de novo
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001994798.1
First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021 |
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 69
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002518630.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Jun 01, 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: SCV002759108.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
Published functional studies demonstrate that this variant negatively affects channel voltage-dependent activation and slows inactivation (Helbig et al., 2018); Not observed at significant frequency in … (more)
Published functional studies demonstrate that this variant negatively affects channel voltage-dependent activation and slows inactivation (Helbig et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31064215, 17660294, 23934111, 33746731, 31175295, 33726816, 30343943) (less)
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Pathogenic
(Aug 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 69
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002811734.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Mar 07, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000742095.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Profound global developmental delay (present) , Poor head control (present) , Visual impairment (present) , Infantile spasms (present) , Macrocephalus (present) , Short stature (present) … (more)
Profound global developmental delay (present) , Poor head control (present) , Visual impairment (present) , Infantile spasms (present) , Macrocephalus (present) , Short stature (present) , Arthrogryposis multiplex congenita (present) , Metatarsus adductus (present) , Flexion contracture (present) , Hypertonia (present) , Feeding difficulties (present) , Constipation (present) , Laryngomalacia (present) , Gastroesophageal reflux (present) , Abnormal posturing (present) (less)
Sex: male
Ethnicity/Population group: African American
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Pathogenic
(Mar 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 69
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Acibadem Labgen Genetic Diagnostic Center
Accession: SCV003842183.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Number of individuals with the variant: 1
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 69
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004179595.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Aug 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001589381.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CACNA1E function (PMID: 30343943). Advanced modeling … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CACNA1E function (PMID: 30343943). 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 CACNA1E protein function. ClinVar contains an entry for this variant (Variation ID: 521483). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 30343943). 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 threonine, which is neutral and polar, at codon 702 of the CACNA1E protein (p.Ala702Thr). (less)
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Pathogenic
(Nov 18, 2020)
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no assertion criteria provided
Method: literature only
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DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 69
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000882419.2
First in ClinVar: Jan 22, 2019 Last updated: Nov 21, 2020 |
Comment on evidence:
In 6 unrelated patients (patients 19-24) with developmental and epileptic encephalopathy-69 (DEE69; 618285), Helbig et al. (2018) identified a de novo heterozygous c.2104G-A transition (c.2104G-A, … (more)
In 6 unrelated patients (patients 19-24) with developmental and epileptic encephalopathy-69 (DEE69; 618285), Helbig et al. (2018) identified a de novo heterozygous c.2104G-A transition (c.2104G-A, NM_000721.3) in the CACNA1E gene, resulting in an ala702-to-thr (A702T) substitution in the cytoplasmic end of the S6 transmembrane segment of domain II. The mutation, which was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases. In vitro functional expression studies showed that the mutation resulted in a gain-of-function effect with increased channel activation compared to wildtype. The patients had onset of various types of seizures between 3 and 6 months of age. EEG showed multifocal discharges and hypsarrhythmia. (less)
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Likely pathogenic
(Nov 01, 2018)
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no assertion criteria provided
Method: literature only
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Early infantile epileptic encephalopathy with suppression bursts
Affected status: yes
Allele origin:
de novo
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Yale Center for Mendelian Genomics, Yale University
Study: Yale Center for Mendelian Genomics
Accession: SCV002106537.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022 |
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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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De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias. | Helbig KL | American journal of human genetics | 2018 | PMID: 30343943 |
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 |
De novo mutations in epileptic encephalopathies. | Epi4K Consortium | Nature | 2013 | PMID: 23934111 |
The role of distal S6 hydrophobic residues in the voltage-dependent gating of CaV2.3 channels. | Raybaud A | The Journal of biological chemistry | 2007 | PMID: 17660294 |
Text-mined citations for rs12131800 ...
HelpRecord last updated Mar 30, 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.