ClinVar Genomic variation as it relates to human health
NM_001127222.2(CACNA1A):c.4988G>A (p.Arg1663Gln)
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.
Pathogenic(7); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001127222.2(CACNA1A):c.4988G>A (p.Arg1663Gln)
Variation ID: 68432 Accession: VCV000068432.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.13 19: 13235693 (GRCh38) [ NCBI UCSC ] 19: 13346507 (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 Oct 22, 2013 May 1, 2024 Sep 12, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001127222.2:c.4988G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001120694.1:p.Arg1663Gln missense NM_000068.4:c.5006G>A NP_000059.3:p.Arg1669Gln missense NM_001127221.2:c.4991G>A NP_001120693.1:p.Arg1664Gln missense NM_001174080.2:c.4997G>A NP_001167551.1:p.Arg1666Gln missense NM_023035.3:c.5006G>A NP_075461.2:p.Arg1669Gln missense NC_000019.10:g.13235693C>T NC_000019.9:g.13346507C>T NG_011569.1:g.275768G>A LRG_7:g.275768G>A LRG_7t1:c.4991G>A LRG_7p1:p.Arg1664Gln - Protein change
- R1664Q, R1669Q, R1666Q, R1663Q
- Other names
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- Canonical SPDI
- NC_000019.10:13235692:C:T
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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
Help
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
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. |
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Pathogenic (2) |
criteria provided, single submitter
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Feb 23, 2023 | RCV000059302.9 | |
Pathogenic (1) |
no assertion criteria provided
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Nov 30, 2014 | RCV000157057.9 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Sep 12, 2023 | RCV000406556.14 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 20, 2014 | RCV000415457.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 15, 2022 | RCV000653331.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 1, 2017 | RCV000679889.9 | |
Pathogenic (1) |
no assertion criteria provided
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Feb 11, 2019 | RCV000755049.8 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV002273953.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 16, 2019 | RCV002311540.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 7, 2021 | RCV003152591.9 |
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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Likely pathogenic
(May 20, 2014)
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criteria provided, single submitter
Method: clinical testing
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Enlarged cisterna magna
Global developmental delay
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492918.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
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Likely pathogenic
(Jun 16, 2017)
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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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Athena Diagnostics Inc
Accession: SCV000612550.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental delay
Affected status: yes
Allele origin:
de novo
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Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV002559122.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
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Uncertain significance
(Sep 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Episodic ataxia type 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Baylor Genetics
Accession: SCV000807290.2
First in ClinVar: Sep 17, 2018 Last updated: Dec 11, 2022 |
Comment:
This mutation has been previously reported as disease-causing and was found four times in our laboratory as de novo findings in affected individuals.
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 42
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV003841211.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
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Pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Spinocerebellar ataxia type 6
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003841799.1
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: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068432). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 28742085). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16325861, 28742085). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Cerebral palsy (present) , Inability to walk (present) , Absent speech (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:
de novo
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Pediatric Department, Xiangya Hospital, Central South University
Accession: SCV003930353.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Clinical Features:
Focal seizures (present) , profound intellectual disability (present) , progressive cerebellar atrophy (present) , ataxia. (present)
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Pathogenic
(Aug 14, 2023)
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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: SCV000329829.6
First in ClinVar: Dec 06, 2016 Last updated: Aug 24, 2023 |
Comment:
Published functional studies demonstrate a damaging effect by significantly impairing the function of the protein (PMID: 28742085); Not observed at significant frequency in large population … (more)
Published functional studies demonstrate a damaging effect by significantly impairing the function of the protein (PMID: 28742085); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28742085, 16325861, 24486772, 32429945, 32637629, 37555011, 33349592, 34068417) (less)
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Pathogenic
(Sep 12, 2023)
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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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Revvity Omics, Revvity
Accession: SCV003813096.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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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: SCV000775210.5
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects CACNA1A function (PMID: 28742085). 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: 68432). This missense change has been observed in individual(s) with early onset ataxia (PMID: 16325861, 28742085). 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 arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1664 of the CACNA1A protein (p.Arg1664Gln). (less)
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Likely pathogenic
(Apr 16, 2019)
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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: SCV000846881.6
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
The p.R1664Q variant (also known as c.4991G>A), located in coding exon 32 of the CACNA1A gene, results from a G to A substitution at nucleotide … (more)
The p.R1664Q variant (also known as c.4991G>A), located in coding exon 32 of the CACNA1A gene, results from a G to A substitution at nucleotide position 4991. The arginine at codon 1664 is replaced by glutamine, an amino acid with highly similar properties. The variant disrupts the R2 position of the voltage sensing motif in the voltage sensing domain which is known to be crucial for proper gating (Bezanilla F. Nat. Rev. Mol. Cell Biol., 2008 Apr;9:323-32; Chamberlin A et al. J. Mol. Biol., 2015 Jan;427:131-45). In one study, this alteration was identified as a de novo occurrence in four individuals with severe early onset ataxia, global developmental delay, hypotonia, and ophthalmologic abnormalities. In addition, two studies performed in drosophilla showed that this alteration acts as a loss of function mutation and only partially rescues lethality (Oriel C et al. Int J Mol Sci, 2018 Jul;19:; Luo X et al. PLoS Genet., 2017 Jul;13:e1006905). In another study, this variant was identified to be de novo with early onset, non-fluctuating limb and trunk ataxia (Tonelli A et al. J. Neurol. Sci., 2006 Feb;241:13-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Nov 30, 2014)
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no assertion criteria provided
Method: clinical testing
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Chronic and progressive ataxia
Affected status: yes
Allele origin:
uniparental
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Mendelics
Accession: SCV000199322.2
First in ClinVar: Feb 02, 2015 Last updated: Feb 15, 2015 |
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Pathogenic
(-)
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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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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001963387.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(Feb 11, 2019)
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no assertion criteria provided
Method: research
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Ataxia _ Neurologic (child onset)
Non-progressive congenital cerebellar ataxia (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea
Accession: SCV000882749.1
First in ClinVar: Feb 17, 2019 Last updated: Feb 17, 2019 |
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Likely pathogenic
(-)
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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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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001968847.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Not Provided
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Brain Gene Registry
Accession: SCV002760025.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
Variant interpreted as Pathogenic and reported on 12-08-2021 by Lab or GTR ID 500031. Assertions are reported exactly as they appear on the patient provided … (more)
Variant interpreted as Pathogenic and reported on 12-08-2021 by Lab or GTR ID 500031. 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 John Constantino MD PhD 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:
Short stature (present) , Hyperthyroidism (present) , Abnormality of eye movement (present) , Hypermetropia (present) , Cognitive impairment (present) , Abnormality of coordination (present) , … (more)
Short stature (present) , Hyperthyroidism (present) , Abnormality of eye movement (present) , Hypermetropia (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Abnormal aggressive, impulsive or violent behavior (present) , Compulsive behaviors (present) , Abnormal muscle physiology (present) , Abnormal morphology of the pelvis musculature (present) , Feeding difficulties (present) , Abnormal large intestine morphology (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2021-12-08
Testing laboratory interpretation: Pathogenic
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not provided
(-)
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no classification provided
Method: not provided
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Spinocerebellar ataxia 6
Affected status: not provided
Allele origin:
not provided
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UniProtKB/Swiss-Prot
Accession: SCV000090860.1
First in ClinVar: Oct 22, 2013 Last updated: Oct 22, 2013
Comment:
The proband presented with not fluctuating ataxia with a quite early age of onset (PubMed 16325861)
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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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Recent Developments in Using Drosophila as a Model for Human Genetic Disease. | Oriel C | International journal of molecular sciences | 2018 | PMID: 30011838 |
Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially. | Luo X | PLoS genetics | 2017 | PMID: 28742085 |
Mapping the gating and permeation pathways in the voltage-gated proton channel Hv1. | Chamberlin A | Journal of molecular biology | 2015 | PMID: 25481746 |
Episodic Ataxia Type 2 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2015 | PMID: 20301674 |
A novel missense mutation in CACNA1A evaluated by in silico protein modeling is associated with non-episodic spinocerebellar ataxia with slow progression. | Bürk K | European journal of medical genetics | 2014 | PMID: 24486772 |
How membrane proteins sense voltage. | Bezanilla F | Nature reviews. Molecular cell biology | 2008 | PMID: 18354422 |
Molecular basis of inherited calcium channelopathies: role of mutations in pore-forming subunits. | McKeown L | Acta pharmacologica Sinica | 2006 | PMID: 16787562 |
Early onset, non fluctuating spinocerebellar ataxia and a novel missense mutation in CACNA1A gene. | Tonelli A | Journal of the neurological sciences | 2006 | PMID: 16325861 |
Text-mined citations for rs121908247 ...
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.