ClinVar Genomic variation as it relates to human health
NM_001205293.3(CACNA1E):c.1054G>A (p.Gly352Arg)
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.1054G>A (p.Gly352Arg)
Variation ID: 265066 Accession: VCV000265066.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q25.3 1: 181651440 (GRCh38) [ NCBI UCSC ] 1: 181620576 (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 7, 2017 Feb 14, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001205293.3:c.1054G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001192222.1:p.Gly352Arg missense NM_000721.4:c.1054G>A NP_000712.2:p.Gly352Arg missense NM_001205294.2:c.1054G>A NP_001192223.1:p.Gly352Arg missense NC_000001.11:g.181651440G>A NC_000001.10:g.181620576G>A NG_050616.1:g.173130G>A - Protein change
- G352R
- Other names
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- Canonical SPDI
- NC_000001.11:181651439: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 |
1966 | 1997 |
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 (3) |
criteria provided, multiple submitters, no conflicts
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Jan 19, 2024 | RCV000255319.10 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2023 | RCV000754086.13 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 15, 2018 | RCV001266668.3 | |
Likely pathogenic (1) |
no assertion criteria provided
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Nov 1, 2018 | RCV001849352.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 29, 2023 | RCV003417866.4 |
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 03, 2019)
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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,
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001150035.2
First in ClinVar: Feb 03, 2020 Last updated: Aug 16, 2020 |
Observation 1:
Clinical Features:
Cerebral atrophy (present) , Increased circulating lactate concentration (present) , Seizure (present) , Decreased activity of mitochondrial complex IV (present) , Hypotonia (present) , Decreased … (more)
Cerebral atrophy (present) , Increased circulating lactate concentration (present) , Seizure (present) , Decreased activity of mitochondrial complex IV (present) , Hypotonia (present) , Decreased activity of mitochondrial complex I (present) , Global developmental delay (present) (less)
Sex: female
Tissue: blood
Observation 2:
Clinical Features:
High, narrow palate (present) , Scoliosis (present) , Dystonic disorder (present) , Global developmental delay (present) , Ulnar deviation of the hand or of fingers … (more)
High, narrow palate (present) , Scoliosis (present) , Dystonic disorder (present) , Global developmental delay (present) , Ulnar deviation of the hand or of fingers of the hand (present) , Multiple joint contractures (present) , Epileptic encephalopathy (present) , Developmental regression (present) , Pectus carinatum (present) , Bilateral talipes equinovarus (present) , Seizure (present) (less)
Sex: male
Tissue: blood
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 69
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429013.2
First in ClinVar: Aug 16, 2020 Last updated: Mar 05, 2022 |
Comment:
_x000D_ Criteria applied: PS2_VSTR, PS4_MOD, PM1, PM2_SUP, PP3
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Likely pathogenic
(May 15, 2018)
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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: SCV001444845.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Infantile spasms (present) , Seizures (present) , Profound global developmental delay (present) , Poor suck (present) , Constipation (present) , Visual impairment (present) , Nystagmus … (more)
Infantile spasms (present) , Seizures (present) , Profound global developmental delay (present) , Poor suck (present) , Constipation (present) , Visual impairment (present) , Nystagmus (present) , Global developmental delay (present) , Feeding difficulties (present) , Muscular hypotonia (present) , Gastrostomy tube feeding in infancy (present) , Gastroesophageal reflux (present) , Abnormality of vitamin B12 metabolism (present) (less)
Sex: female
Ethnicity/Population group: Hispanic
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Pathogenic
(Aug 31, 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: SCV003802795.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
Comment:
The CACNA1E c.1054G>A (p.Gly352Arg) missense variant results in substitution of glycine at amino acid position 352 with arginine. This variant has been reported in a … (more)
The CACNA1E c.1054G>A (p.Gly352Arg) missense variant results in substitution of glycine at amino acid position 352 with arginine. This variant has been reported in a heterozygous state in at least 13 individuals with developmental and epileptic encephalopathy (PMID: 30343943; PMID: 32695065; PMID: 33776624; PMID: 35937981). Of these, all are WES or WGS studies and five have confirmed de novo inheritance. This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.1054G>A (p.Gly352Arg) variant is classified as pathogenic for CACNA1E-related developmental and epileptic encephalopathy. (less)
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Pathogenic
(Dec 10, 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: SCV000321496.8
First in ClinVar: Oct 10, 2016 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed 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: 30343943, 32695065) (less)
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Pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 69
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003842098.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.69). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265066). The variant has been previously reported as de novo in a similarly affected individual (PMID: 30343943, 30343943). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 30343943). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Epileptic spasm (present) , Seizure (present) , Hypsarrhythmia (present) , Infantile spasms (present) , Developmental regression (present) , Spastic tetraplegia (present) , Cerebral palsy (present) … (more)
Epileptic spasm (present) , Seizure (present) , Hypsarrhythmia (present) , Infantile spasms (present) , Developmental regression (present) , Spastic tetraplegia (present) , Cerebral palsy (present) , Hip subluxation (present) , Esotropia (present) (less)
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Pathogenic
(Oct 23, 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:
de novo
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Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital
Accession: SCV004046876.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
This heterozygous mis-sense variant is identified in a 9 month female with perinatal asphyxia, myoclonic seizures, DD, hypotonia, MRI Brain with T2 hyper-intensities in globus … (more)
This heterozygous mis-sense variant is identified in a 9 month female with perinatal asphyxia, myoclonic seizures, DD, hypotonia, MRI Brain with T2 hyper-intensities in globus pallidus. This nucleotide change is absent in gnomAD database [PM2]. Insilico prediction [REVEL=0.91] predicts deleterious nature of this variant. A clinvar entry for this variant is available. This variant is submitted to clinvar database [Variation ID: 265066] with “Pathogenic/Likely Pathogenic” interpretation by multiple submitter [PP5]. Parental segregation confirmed the de-novo status of this variant [PM6]. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic" (less)
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Pathogenic
(May 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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CACNA1E-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004106146.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The CACNA1E c.1054G>A variant is predicted to result in the amino acid substitution p.Gly352Arg. This variant has been reported as a recurrent de novo finding … (more)
The CACNA1E c.1054G>A variant is predicted to result in the amino acid substitution p.Gly352Arg. This variant has been reported as a recurrent de novo finding in individuals with autosomal dominant epileptic encephalopathy (Helbig et al. 2018. PubMed ID: 30343943, Table 1; OMIM #618285). Clinical features in affected individuals included seizures, hypotonia, hypertonia, dystonia, MRI abnormalities, profound developmental delay, macrocephaly, and contractures. This variant was also described as likely pathogenic in an individual who was tested as part of an epilepsy panel, but the phenotype of this patient was not given (Won et al. 2020. PubMed ID: 32695065). This variant is absent in the gnomAD population database, indicating that it is very rare. In ClinVar, this variant is interpreted as pathogenic and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/265066/). In summary, this variant is interpreted as pathogenic. (less)
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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: SCV004179579.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Jan 19, 2024)
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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: SCV003256100.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 352 of the CACNA1E protein (p.Gly352Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 352 of the CACNA1E protein (p.Gly352Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 30343943). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265066). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic. (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: SCV000882421.2
First in ClinVar: Jan 22, 2019 Last updated: Nov 21, 2020 |
Comment on evidence:
In 9 unrelated patients (patients 3-11) with developmental and epileptic encephalopathy-69 (DEE69; 618285), Helbig et al. (2018) identified a de novo heterozygous c.1054G-A transition (c.1054G-A, … (more)
In 9 unrelated patients (patients 3-11) with developmental and epileptic encephalopathy-69 (DEE69; 618285), Helbig et al. (2018) identified a de novo heterozygous c.1054G-A transition (c.1054G-A, NM_000721.3) in the CACNA1E gene, resulting in a gly352-to-arg (G352R) substitution in the cytoplasmic end of the S6 transmembrane segment of domain I. 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. Functional expression studies of the variant were not performed. The patients had onset of various types of seizures between 2 months and 3 years of age. (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: SCV002106530.1 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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Clinically available testing options resulting in diagnosis in post-exome clinic at one medical center. | Baker EK | Frontiers in genetics | 2022 | PMID: 35937981 |
Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy. | Ortiz Cabrera NV | Molecular syndromology | 2021 | PMID: 33776624 |
Reanalysis of Genomic Sequencing Results in a Clinical Laboratory: Advantages and Limitations. | Won D | Frontiers in neurology | 2020 | PMID: 32695065 |
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 |
Text-mined citations for rs886039323 ...
HelpRecord last updated Apr 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.