ClinVar Genomic variation as it relates to human health
NM_001127222.2(CACNA1A):c.835C>T (p.Arg279Cys)
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_001127222.2(CACNA1A):c.835C>T (p.Arg279Cys)
Variation ID: 545691 Accession: VCV000545691.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.13 19: 13359749 (GRCh38) [ NCBI UCSC ] 19: 13470563 (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 Jul 2, 2018 May 1, 2024 Oct 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001127222.2:c.835C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001120694.1:p.Arg279Cys missense NM_000068.4:c.835C>T NP_000059.3:p.Arg279Cys missense NM_001127221.2:c.835C>T NP_001120693.1:p.Arg279Cys missense NM_001174080.2:c.835C>T NP_001167551.1:p.Arg279Cys missense NM_023035.1:c.835C>T NM_023035.3:c.835C>T NP_075461.2:p.Arg279Cys missense NC_000019.10:g.13359749G>A NC_000019.9:g.13470563G>A NG_011569.1:g.151712C>T LRG_7:g.151712C>T LRG_7t1:c.835C>T LRG_7p1:p.Arg279Cys - Protein change
- R279C
- Other names
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- Canonical SPDI
- NC_000019.10:13359748: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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- Links
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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CACNA1A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3375 | 3670 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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 (1) |
no assertion criteria provided
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Jan 10, 2018 | RCV000656726.1 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Jul 29, 2022 | RCV000991686.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 15, 2022 | RCV001035721.5 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 22, 2021 | RCV001849186.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 20, 2022 | RCV002227194.1 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 1, 2023 | RCV003230272.2 | |
not provided (1) |
no classification provided
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- | RCV003233795.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 6, 2023 | RCV004025995.1 |
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
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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
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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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Likely pathogenic
(Mar 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 52
Episodic ataxia type 2 Migraine, familial hemiplegic, 1 Spinocerebellar ataxia type 6
Affected status: yes
Allele origin:
maternal
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Wendy Chung Laboratory, Columbia University Medical Center
Accession: SCV002506548.1
First in ClinVar: May 07, 2022 Last updated: May 07, 2022 |
Clinical Features:
Hereditary episodic ataxia (present) , Autistic behavior (present) , Neurodevelopmental delay (present)
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Likely pathogenic
(Jul 29, 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: SCV001817277.3
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023 |
Comment:
Identified in multiple patients with episodic ataxia in published literature (Maksemous et al., 2016; Tomlinson et al., 2016; Coutelier et al., 2017); In silico analysis … (more)
Identified in multiple patients with episodic ataxia in published literature (Maksemous et al., 2016; Tomlinson et al., 2016; Coutelier et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23344743, 30142438, 27066515, 28444220, 26912519, 31654490, 32899500, 34263451, 35401678, 35395208, 34102571) (less)
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Likely pathogenic
(Jun 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 42
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV003928013.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Clinical Features:
Delayed speech and language development (present) , Global developmental delay (present) , Motor delay (present) , Attention deficit hyperactivity disorder (present) , Cognitive impairment (present)
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Pathogenic
(Jan 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 42
Affected status: yes
Allele origin:
paternal
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Pediatric Department, Xiangya Hospital, Central South University
Accession: SCV003930354.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Clinical Features:
Focal seizures (present) , severe intellectual disability (present) , autism spectrum disorder (present) , ataxia. (present)
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Pathogenic
(Jun 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 42
Episodic ataxia type 2
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001199055.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. 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 CACNA1A protein function. ClinVar contains an entry for this variant (Variation ID: 545691). This missense change has been observed in individuals with CACNA1A-related conditions (PMID: 26912519, 27066515, 28444220, 30142438). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 279 of the CACNA1A protein (p.Arg279Cys). (less)
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Pathogenic
(Oct 06, 2023)
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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: SCV004915157.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.835C>T (p.R279C) alteration is located in exon 6 (coding exon 6) of the CACNA1A gene. This alteration results from a C to T substitution … (more)
The c.835C>T (p.R279C) alteration is located in exon 6 (coding exon 6) of the CACNA1A gene. This alteration results from a C to T substitution at nucleotide position 835, causing the arginine (R) at amino acid position 279 to be replaced by a cysteine (C)._x000D_ _x000D_ ; however, it is unlikely to be causative of CACN1A-related spinocerebellar ataxia. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in one individual and has been reported as heterozygous in three individuals with features consistent with episodic ataxia, type 2 (Tomlinson, 2016; Maksemous, 2016; Angelini, 2019; Waters, 2019; Hommersom, 2022). Additionally, this variant has been reported in multiple individuals with features consistent with CACNA1A-related early onset ataxia (Angelini, 2019; Ghorbani, 2022; Lipman, 2022; Kessi, 2023). One study has shown this variant to segregate with both episodic ataxia, type 2 and CACNA1A-related neurologic disorders within the same family with incomplete penetrance (Angelini, 2019). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This 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
(Jan 10, 2018)
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no assertion criteria provided
Method: clinical testing
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None
None None (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
maternal
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Laboratoire de Genetique Moleculaire, Centre Hospitalier Universitaire de Bordeaux
Accession: SCV000778839.1
First in ClinVar: Jul 02, 2018 Last updated: Jul 02, 2018 |
Comment:
The Arg279Cys variant in CACNA1A has been reported in a family with episodic ataxia type 2 by Maksemous et al, 2016. This variant is absent … (more)
The Arg279Cys variant in CACNA1A has been reported in a family with episodic ataxia type 2 by Maksemous et al, 2016. This variant is absent in GnomAD and ExAC database. (less)
Number of individuals with the variant: 10
Sex: male
Geographic origin: France
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Pathogenic
(Jul 22, 2021)
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no assertion criteria provided
Method: research
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Spinocerebellar ataxia type 6
Affected status: yes
Allele origin:
de novo
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O&I group, Department of Genetics, University Medical Center of Groningen
Accession: SCV001960823.1
First in ClinVar: Mar 23, 2022 Last updated: Mar 23, 2022 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Spinocerebellar ataxia type 6
Episodic ataxia type 2 Migraine, familial hemiplegic, 1
Affected status: yes
Allele origin:
unknown
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GenomeConnect - Brain Gene Registry
Accession: SCV003931145.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Comment:
Variant classified as Likely pathogenic and reported on 02-23-2021 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect … (more)
Variant classified as Likely pathogenic and reported on 02-23-2021 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne?from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less)
Clinical Features:
Abnormality of eye movement (present) , Myopia (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Memory impairment (present) … (more)
Abnormality of eye movement (present) , Myopia (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Memory impairment (present) , Movement disorder (present) , Autistic behavior (present) , Motor stereotypies (present) , Anxiety (present) , Depression (present) , Hyperhidrosis (present) , Hyperextensible skin (present) , Joint hypermobility (present) , Developmental dysplasia of the hip (present) , Abnormal muscle physiology (present) , Cardiac arrhythmia (present) , Abnormality of the cardiovascular system (present) , Asthma (present) , Gastrointestinal dysmotility (present) , Abnormal intestine morphology (present) , Recurrent infections (present) , Gingivitis (present) (less)
Indication for testing: Diagnostic
Age: 20-29 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2021-02-23
Testing laboratory interpretation: Likely pathogenic
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Uncertain significance
(Oct 30, 2018)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics Inc
Accession: SCV001143349.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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The genotype-phenotype correlations of the CACNA1A-related neurodevelopmental disorders: a small case series and literature reviews. | Kessi M | Frontiers in molecular neuroscience | 2023 | PMID: 37555011 |
Clinical and genetic characterization of CACNA1A-related disease. | Lipman AR | Clinical genetics | 2022 | PMID: 35722745 |
Feasibility of Follow-Up Studies and Reclassification in Spinocerebellar Ataxia Gene Variants of Unknown Significance. | Ghorbani F | Frontiers in genetics | 2022 | DOI: 10.3389/fgene.2022.782685 |
Feasibility of Follow-Up Studies and Reclassification in Spinocerebellar Ataxia Gene Variants of Unknown Significance. | Ghorbani F | Frontiers in genetics | 2022 | PMID: 35401678 |
The complexities of CACNA1A in clinical neurogenetics. | Hommersom MP | Journal of neurology | 2022 | PMID: 34806130 |
HSD10 mitochondrial disease: p.Leu122Val variant, mild clinical phenotype, and founder effect in French-Canadian patients from Quebec. | Waters PJ | Molecular genetics & genomic medicine | 2019 | PMID: 31654490 |
Major intra-familial phenotypic heterogeneity and incomplete penetrance due to a CACNA1A pathogenic variant. | Angelini C | European journal of medical genetics | 2019 | PMID: 30142438 |
A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies. | Coutelier M | Brain : a journal of neurology | 2017 | PMID: 28444220 |
Next-generation sequencing identifies novel CACNA1A gene mutations in episodic ataxia type 2. | Maksemous N | Molecular genetics & genomic medicine | 2016 | PMID: 27066515 |
In vivo impact of presynaptic calcium channel dysfunction on motor axons in episodic ataxia type 2. | Tomlinson SE | Brain : a journal of neurology | 2016 | PMID: 26912519 |
Text-mined citations for rs1555773764 ...
HelpRecord last updated May 01, 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.