The CACNA1G c. 5144G>A variant is classified as a PATHOGENIC variant (PS4, PS3, PP1_Strong, PP3, PP5) The variant is a single nucleotide change from a guanine to an adenine at position 5144 which is predicted to change the Arginine at position 1715 in the protein to Histidine. The variant is in exon 29 and is located in protein domains: ion transport domain, and Polycystin cation channel, of the CACNA1G gene. This variant is a recurrent pathogenic variant in the CACNA1G gene, and it has been previously reported in many individuals with Cerebellar ataxias in heterozygoys state (PMID: 26456284, 26715324, 28490766, 29629410) (PS4). This variant is in dbSNP (rs755221106) but is absent from population databases. In vitro functonal studies have demonstrated that this variant had resulted in a significant shift of the steady-state activation curve towards more positive membrane potential values, whereas the inactivation curve had a higher slope factor, supporting the damaging effect on the gene or gene product (PMID: 26456284, 26715324) (PS3). Multiple pedigrees of Cerebellar ataxia-affected families with this variant has been previously reported showing segregation of this variant with the disorder (PMID: PMID: 26456284, 26715324, 28490766, 29629410) (PP1_Strong). The variant has been reported in the ClinVar (Variation ID: 221981) and HGMD (Accession: CM1511857) as Pathogenic (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3).
ClinVar Genomic variation as it relates to human health
NM_018896.5(CACNA1G):c.5144G>A (p.Arg1715His)
Germline
Classification
Help
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.
(8)
Help
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_018896.5(CACNA1G):c.5144G>A (p.Arg1715His)
Variation ID: 221981 Accession: VCV000221981.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q21.33 17: 50617560 (GRCh38) [ NCBI UCSC ] 17: 48694921 (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 Feb 14, 2016 Mar 4, 2023 May 13, 2022 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_018896.5:c.5144G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_061496.2:p.Arg1715His missense NM_001256324.2:c.5090G>A NP_001243253.1:p.Arg1697His missense NM_001256325.2:c.5165G>A NP_001243254.1:p.Arg1722His missense NM_001256326.2:c.5009G>A NP_001243255.1:p.Arg1670His missense NM_001256327.2:c.5144G>A NP_001243256.1:p.Arg1715His missense NM_001256328.2:c.5090G>A NP_001243257.1:p.Arg1697His missense NM_001256329.2:c.5042G>A NP_001243258.1:p.Arg1681His missense NM_001256330.2:c.5009G>A NP_001243259.1:p.Arg1670His missense NM_001256331.2:c.4988G>A NP_001243260.1:p.Arg1663His missense NM_001256332.2:c.4973G>A NP_001243261.1:p.Arg1658His missense NM_001256333.2:c.5144G>A NP_001243262.1:p.Arg1715His missense NM_001256334.2:c.5111G>A NP_001243263.1:p.Arg1704His missense NM_001256359.2:c.5063G>A NP_001243288.1:p.Arg1688His missense NM_001256360.2:c.5036G>A NP_001243289.1:p.Arg1679His missense NM_001256361.2:c.5030G>A NP_001243290.1:p.Arg1677His missense NM_198376.3:c.5042G>A NP_938190.1:p.Arg1681His missense NM_198377.3:c.5111G>A NP_938191.2:p.Arg1704His missense NM_198378.3:c.5111G>A NP_938192.1:p.Arg1704His missense NM_198379.3:c.5042G>A NP_938193.1:p.Arg1681His missense NM_198380.3:c.5111G>A NP_938194.1:p.Arg1704His missense NM_198382.3:c.5075G>A NP_938196.1:p.Arg1692His missense NM_198383.3:c.5075G>A NP_938197.1:p.Arg1692His missense NM_198384.3:c.5144G>A NP_938198.1:p.Arg1715His missense NM_198385.3:c.5144G>A NP_938199.1:p.Arg1715His missense NM_198386.3:c.5090G>A NP_938200.1:p.Arg1697His missense NM_198387.3:c.5042G>A NP_938201.1:p.Arg1681His missense NM_198388.3:c.5021G>A NP_938202.1:p.Arg1674His missense NM_198396.3:c.5042G>A NP_938406.1:p.Arg1681His missense NR_046054.2:n.5889G>A non-coding transcript variant NR_046055.2:n.5856G>A non-coding transcript variant NR_046056.2:n.5835G>A non-coding transcript variant NR_046057.2:n.5820G>A non-coding transcript variant NR_046058.2:n.5766G>A non-coding transcript variant NC_000017.11:g.50617560G>A NC_000017.10:g.48694921G>A NG_032024.1:g.61493G>A O43497:p.Arg1715His - Protein change
- R1715H, R1670H, R1681H, R1704H, R1677H, R1688H, R1697H, R1663H, R1658H, R1674H, R1679H, R1692H, R1722H
- Other names
- -
- Canonical SPDI
- NC_000017.11:50617559: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.
- -
- Links
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 |
1138 | 1184 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 5, 2021 | RCV000207440.10 | |
|
CACNA1G-related disorder
|
not provided (1) |
no classification provided
|
- | RCV000509294.2 |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000763013.3 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 13, 2022 | RCV001267950.5 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jun 02, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Spinocerebellar ataxia 42
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000593821.1
First in ClinVar: Feb 14, 2016 Last updated: Feb 14, 2016 |
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Spinocerebellar ataxia type 42
Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893458.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446472.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Cerebellar ataxia (present) , Dysarthria (present) , Gait ataxia (present) , Bradykinesia (present) , Tremor (present)
Sex: male
|
|
|
Pathogenic
(Jan 04, 2021)
|
criteria provided, single submitter
Method: research
|
Spinocerebellar ataxia type 42
Affected status: yes
Allele origin:
inherited
|
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris
Accession: SCV001519114.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
|
|
|
Pathogenic
(Aug 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Spinocerebellar ataxia type 42
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556746.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
Comment:
The CACNA1G c. 5144G>A variant is classified as a PATHOGENIC variant (PS4, PS3, PP1_Strong, PP3, PP5) The variant is a single nucleotide change from a … (more)
The CACNA1G c. 5144G>A variant is classified as a PATHOGENIC variant (PS4, PS3, PP1_Strong, PP3, PP5) The variant is a single nucleotide change from a guanine to an adenine at position 5144 which is predicted to change the Arginine at position 1715 in the protein to Histidine. The variant is in exon 29 and is located in protein domains: ion transport domain, and Polycystin cation channel, of the CACNA1G gene. This variant is a recurrent pathogenic variant in the CACNA1G gene, and it has been previously reported in many individuals with Cerebellar ataxias in heterozygoys state (PMID: 26456284, 26715324, 28490766, 29629410) (PS4). This variant is in dbSNP (rs755221106) but is absent from population databases. In vitro functonal studies have demonstrated that this variant had resulted in a significant shift of the steady-state activation curve towards more positive membrane potential values, whereas the inactivation curve had a higher slope factor, supporting the damaging effect on the gene or gene product (PMID: 26456284, 26715324) (PS3). Multiple pedigrees of Cerebellar ataxia-affected families with this variant has been previously reported showing segregation of this variant with the disorder (PMID: PMID: 26456284, 26715324, 28490766, 29629410) (PP1_Strong). The variant has been reported in the ClinVar (Variation ID: 221981) and HGMD (Accession: CM1511857) as Pathogenic (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3). (less)
|
|
|
Pathogenic
(May 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002599867.2
First in ClinVar: Nov 13, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect on membrane potential dependency (Coutelier et al., 2015; Morino et al., 2015); Not observed at significant frequency in … (more)
Published functional studies demonstrate a damaging effect on membrane potential dependency (Coutelier et al., 2015; Morino et al., 2015); 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: 29915382, 34426522, 30200108, 29474447, 35054808, 29421541, 31892274, 30842224, 32878331, 32638069, 34248568, 31999455, 34220096, 33746731, 31229688, 33243296, 31836334, 28490766, 26715324, 33624863, 31692161, 26456284, 29629410, 33163565, 31217264) (less)
|
|
|
Pathogenic
(Aug 14, 2018)
|
no assertion criteria provided
Method: literature only
|
SPINOCEREBELLAR ATAXIA 42
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000262713.2
First in ClinVar: Feb 14, 2016 Last updated: Feb 14, 2016 |
Comment on evidence:
In affected members of 3 unrelated French families with spinocerebellar ataxia-42 (SCA42; 616795), Coutelier et al. (2015) identified a heterozygous c.5144G-A transition (c.5144G-A, NM_018896.4) in … (more)
In affected members of 3 unrelated French families with spinocerebellar ataxia-42 (SCA42; 616795), Coutelier et al. (2015) identified a heterozygous c.5144G-A transition (c.5144G-A, NM_018896.4) in the CACNA1G gene, resulting in an arg1715-to-his (R1715H) substitution at a highly conserved residue in the S4 segment in domain IV of the channel, which contains the voltage-sensing region. The mutation in the first family (AAD-SAL-233) was found by linkage analysis combined with whole-exome sequencing and was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family and was not found in the dbSNP (build 137), Exome Variant Server, or ExAC databases. The mutations in the other 2 families (AAD-GRE-319 and AAD-SAL-454) were found by screening of a large number of probands with a similar disorder; the mutation segregated with the phenotype in both families. Haplotype analysis excluded a founder effect all 3 families. In vitro functional expression studies in HEK293T cells showed that the mutation resulted in a significant shift of the steady-state activation curve towards more positive membrane potential values, whereas the inactivation curve had a higher slope factor. These electrophysiologic studies and computer modeling simulations suggested that mutation resulted in decreased neuronal excitability. Morino et al. (2015) identified heterozygosity for the R1715H mutation in the CACNA1G gene in affected members of 2 unrelated Japanese families with SCA42. The mutations were found by linkage analysis and exome sequencing and were confirmed by Sanger sequencing. The mutation segregated with the disorder in both families, which shared a haplotype containing the mutation. Electrophysiologic studies showed that the mutation shifted the activation to more positive (depolarized) membrane potentials. Inactivation potentials were also shifted to more positive membrane potentials, although the slope factor was not significantly different. The findings indicated that SCA42 is a channelopathy. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
CACNA1G-related disorders
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect, ClinGen
Accession: SCV000607251.1
First in ClinVar: Oct 16, 2017 Last updated: Oct 16, 2017 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Myopia (present) , Tinnitus (present) , Hearing impairment (present) , Depression (present) , Anxiety (present) , Bipolar affective disorder (present) , Abnormality of esophagus morphology … (more)
Myopia (present) , Tinnitus (present) , Hearing impairment (present) , Depression (present) , Anxiety (present) , Bipolar affective disorder (present) , Abnormality of esophagus morphology (present) (less)
Indication for testing: Family Testing
Age: 50-59 years
Sex: female
Testing laboratory: Genetic Services Laboratory,University of Chicago
Date variant was reported to submitter: 2017-07-21
Testing laboratory interpretation: Pathogenic
|
Comment:
Comment:
Published functional studies demonstrate a damaging effect on membrane potential dependency (Coutelier et al., 2015; Morino et al., 2015); 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: 29915382, 34426522, 30200108, 29474447, 35054808, 29421541, 31892274, 30842224, 32878331, 32638069, 34248568, 31999455, 34220096, 33746731, 31229688, 33243296, 31836334, 28490766, 26715324, 33624863, 31692161, 26456284, 29629410, 33163565, 31217264)
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
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. |
Comment:
The CACNA1G c. 5144G>A variant is classified as a PATHOGENIC variant (PS4, PS3, PP1_Strong, PP3, PP5) The variant is a single nucleotide change from a guanine to an adenine at position 5144 which is predicted to change the Arginine at position 1715 in the protein to Histidine. The variant is in exon 29 and is located in protein domains: ion transport domain, and Polycystin cation channel, of the CACNA1G gene. This variant is a recurrent pathogenic variant in the CACNA1G gene, and it has been previously reported in many individuals with Cerebellar ataxias in heterozygoys state (PMID: 26456284, 26715324, 28490766, 29629410) (PS4). This variant is in dbSNP (rs755221106) but is absent from population databases. In vitro functonal studies have demonstrated that this variant had resulted in a significant shift of the steady-state activation curve towards more positive membrane potential values, whereas the inactivation curve had a higher slope factor, supporting the damaging effect on the gene or gene product (PMID: 26456284, 26715324) (PS3). Multiple pedigrees of Cerebellar ataxia-affected families with this variant has been previously reported showing segregation of this variant with the disorder (PMID: PMID: 26456284, 26715324, 28490766, 29629410) (PP1_Strong). The variant has been reported in the ClinVar (Variation ID: 221981) and HGMD (Accession: CM1511857) as Pathogenic (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3).
Comment:
Published functional studies demonstrate a damaging effect on membrane potential dependency (Coutelier et al., 2015; Morino et al., 2015); 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: 29915382, 34426522, 30200108, 29474447, 35054808, 29421541, 31892274, 30842224, 32878331, 32638069, 34248568, 31999455, 34220096, 33746731, 31229688, 33243296, 31836334, 28490766, 26715324, 33624863, 31692161, 26456284, 29629410, 33163565, 31217264)
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Expanding the global prevalence of spinocerebellar ataxia type 42. | Ngo K | Neurology. Genetics | 2018 | PMID: 29629410 |
| SCA42 mutation analysis in a case series of Japanese patients with spinocerebellar ataxia. | Kimura M | Journal of human genetics | 2017 | PMID: 28490766 |
| A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia. | Morino H | Molecular brain | 2015 | PMID: 26715324 |
| A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia. | Coutelier M | American journal of human genetics | 2015 | PMID: 26456284 |
Text-mined citations for rs755221106 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jun 23, 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.