ClinVar Genomic variation as it relates to human health
NM_018896.5(CACNA1G):c.2881G>A (p.Ala961Thr)
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(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_018896.5(CACNA1G):c.2881G>A (p.Ala961Thr)
Variation ID: 280269 Accession: VCV000280269.9
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q21.33 17: 50592063 (GRCh38) [ NCBI UCSC ] 17: 48669424 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 6, 2016 Jul 16, 2023 Jul 10, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_018896.5:c.2881G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_061496.2:p.Ala961Thr missense NM_001256324.2:c.2881G>A NP_001243253.1:p.Ala961Thr missense NM_001256325.2:c.2881G>A NP_001243254.1:p.Ala961Thr missense NM_001256326.2:c.2881G>A NP_001243255.1:p.Ala961Thr missense NM_001256327.2:c.2881G>A NP_001243256.1:p.Ala961Thr missense NM_001256328.2:c.2881G>A NP_001243257.1:p.Ala961Thr missense NM_001256329.2:c.2881G>A NP_001243258.1:p.Ala961Thr missense NM_001256330.2:c.2881G>A NP_001243259.1:p.Ala961Thr missense NM_001256331.2:c.2881G>A NP_001243260.1:p.Ala961Thr missense NM_001256332.2:c.2881G>A NP_001243261.1:p.Ala961Thr missense NM_001256333.2:c.2881G>A NP_001243262.1:p.Ala961Thr missense NM_001256334.2:c.2881G>A NP_001243263.1:p.Ala961Thr missense NM_001256359.2:c.2881G>A NP_001243288.1:p.Ala961Thr missense NM_001256360.2:c.2881G>A NP_001243289.1:p.Ala961Thr missense NM_001256361.2:c.2881G>A NP_001243290.1:p.Ala961Thr missense NM_198376.3:c.2881G>A NP_938190.1:p.Ala961Thr missense NM_198377.3:c.2881G>A NP_938191.2:p.Ala961Thr missense NM_198378.3:c.2881G>A NP_938192.1:p.Ala961Thr missense NM_198379.3:c.2881G>A NP_938193.1:p.Ala961Thr missense NM_198380.3:c.2881G>A NP_938194.1:p.Ala961Thr missense NM_198382.3:c.2881G>A NP_938196.1:p.Ala961Thr missense NM_198383.3:c.2881G>A NP_938197.1:p.Ala961Thr missense NM_198384.3:c.2881G>A NP_938198.1:p.Ala961Thr missense NM_198385.3:c.2881G>A NP_938199.1:p.Ala961Thr missense NM_198386.3:c.2881G>A NP_938200.1:p.Ala961Thr missense NM_198387.3:c.2881G>A NP_938201.1:p.Ala961Thr missense NM_198388.3:c.2881G>A NP_938202.1:p.Ala961Thr missense NM_198396.3:c.2881G>A NP_938406.1:p.Ala961Thr missense NR_046054.2:n.3626G>A non-coding transcript variant NR_046055.2:n.3626G>A non-coding transcript variant NR_046056.2:n.3626G>A non-coding transcript variant NR_046057.2:n.3626G>A non-coding transcript variant NR_046058.2:n.3626G>A non-coding transcript variant NC_000017.11:g.50592063G>A NC_000017.10:g.48669424G>A NG_032024.1:g.35996G>A - Protein change
- A961T
- Other names
- -
- Canonical SPDI
- NC_000017.11:50592062:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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
Help
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. |
|||
CACNA1G | - | - |
GRCh38 GRCh37 |
972 | 1009 |
Conditions - Germline
Condition
Help
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
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. |
---|---|---|---|---|
Pathogenic (1) |
criteria provided, single submitter
|
Oct 20, 2022 | RCV000263291.4 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 10, 2018 | RCV000624028.3 | |
Pathogenic (2) |
criteria provided, single submitter
|
Jul 10, 2023 | RCV000677308.2 | |
Pathogenic (1) |
no assertion criteria provided
|
Jun 4, 2020 | RCV001264626.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Jan 10, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000742235.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Hispanic
|
|
Pathogenic
(Oct 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000330170.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies of the A961T variant demonstrate a gain of function effect by impairing the inactivation of the channel (Chemin et al., 2018); Not … (more)
Published functional studies of the A961T variant demonstrate a gain of function effect by impairing the inactivation of the channel (Chemin et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); 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: 29878067, 31217264, 33098379, 32736238, 31836334, 31785789, 30842224) (less)
|
|
Pathogenic
(Jul 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital
Accession: SCV004011725.1
First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023 |
Comment:
The heterozygous variant c.2881G>A (p.Ala961Thr) has been identified in a proband with global developmental delay, sparse hair, decreased tone, speech defects, inability to handle objects, … (more)
The heterozygous variant c.2881G>A (p.Ala961Thr) has been identified in a proband with global developmental delay, sparse hair, decreased tone, speech defects, inability to handle objects, stranger anxiety, axial hypotonia, limb hypotonia, dystonia and increased levels of glutaric acid on GCMS. This variant has not been reported in gnomAD (aggregated) database (PM2_moderate). Computational tools predict a deleterious effect of the mis-sense variant (PP3_moderate). This variant has been reported previously (PP5_supporting). PMID: 29878067. Segregation in the parents confirms that this is a de-novo variant in the proband. (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: South East Asian
Geographic origin: India
Comment on evidence:
Parents negative for the variant
|
|
Pathogenic
(Aug 14, 2018)
|
no assertion criteria provided
Method: literature only
|
SPINOCEREBELLAR ATAXIA 42, EARLY-ONSET, SEVERE, WITH NEURODEVELOPMENTAL DEFICITS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000803433.1
First in ClinVar: Aug 20, 2018 Last updated: Aug 20, 2018 |
Comment on evidence:
In 3 unrelated girls (subjects 1, 3, and 4) with early-onset severe spinocerebellar ataxia-42 with neurodevelopmental deficits (SCA42ND; 618087), Chemin et al. (2018) identified a … (more)
In 3 unrelated girls (subjects 1, 3, and 4) with early-onset severe spinocerebellar ataxia-42 with neurodevelopmental deficits (SCA42ND; 618087), Chemin et al. (2018) identified a recurrent de novo heterozygous c.2881G-A transition (c.2881G-A, NM_018896.4) in the CACNA1G gene, resulting in an ala961-to-thr (A961T) substitution at a highly conserved residue within the S6 segment that contributes to the pore lining of the channel. The mutation in the first patient was found by whole-exome sequencing and confirmed by Sanger sequencing. The other patients were identified through collaborative sharing of patients with a similar phenotype who underwent exome sequencing. The mutation was not found in the ExAC database. Electrophysiologic studies in HEK293 cells showed that the mutation had markedly slowed inactivation kinetics compared to wildtype and caused increased calcium influx, consistent with a gain of function. Computational modeling of the mutations confirmed that the mutation would promote increased firing activity in deep cerebellar neurons. (less)
|
|
Pathogenic
(Jun 04, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Neurodevelopmental abnormality
Affected status: yes
Allele origin:
de novo
|
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine
Accession: SCV001442905.1
First in ClinVar: Nov 12, 2020 Last updated: Nov 12, 2020 |
Sex: female
|
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 |
---|---|---|---|---|
De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene. | Chemin J | Brain : a journal of neurology | 2018 | PMID: 29878067 |
Text-mined citations for rs886041505 ...
HelpRecord last updated Jul 22, 2023
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.