VCV000585567.34 - ClinVar

NM_001127222.2(CACNA1A):c.3692+1G>A

Germline

Classification

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.

(10)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001127222.2(CACNA1A):c.3692+1G>A

Variation ID: 585567 Accession: VCV000585567.34

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.13 19: 13285067 (GRCh38) [ NCBI UCSC ] 19: 13395881 (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	Oct 20, 2018	Oct 8, 2024	Nov 2, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001127222.2:c.3692+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_000068.4:c.3704+1G>A		splice donor
NM_001127221.2:c.3695+1G>A		splice donor
NM_001174080.2:c.3695+1G>A		splice donor
NM_023035.3:c.3704+1G>A		splice donor
NC_000019.10:g.13285067C>T
NC_000019.9:g.13395881C>T
NG_011569.1:g.226394G>A
LRG_7:g.226394G>A
LRG_7t1:c.3695+1G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000019.10:13285066:C:T

Functional
consequence

The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele
frequency (GMAF)

The 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

The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

dbSNP: rs1315533129

VarSome

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
Gene	OMIM	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.
CACNA1A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3441	3749

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.
not provided	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Feb 16, 2023	RCV000710953.29
Migraine, familial hemiplegic, 1	no classifications from unflagged records (1)	no classifications from unflagged records	Mar 23, 2024	RCV001197888.5
Developmental and epileptic encephalopathy, 42	Likely pathogenic (1)	no assertion criteria provided	Aug 14, 2020	RCV001264752.3
Episodic ataxia type 2	Likely pathogenic (1)	criteria provided, single submitter	Aug 27, 2019	RCV001328546.3
Developmental and epileptic encephalopathy, 42 Episodic ataxia type 2 Migraine, familial hemiplegic, 1 Spinocerebellar ataxia type 6	not provided (1)	no classification provided	-	RCV003458325.2
Developmental and epileptic encephalopathy, 42 Episodic ataxia type 2	Likely pathogenic (1)	criteria provided, single submitter	Nov 2, 2023	RCV003768098.2

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.
Likely pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV001447018.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Gaze-evoked nystagmus (present) , Cerebellar ataxia (present) , Cerebellar atrophy (present) , Progressive cerebellar ataxia (present) Sex: female
Likely pathogenic (Aug 27, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Episodic ataxia type 2 Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001519690.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Likely pathogenic (Feb 21, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002064441.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Pathogenic (Feb 24, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002102761.2 First in ClinVar: Mar 12, 2022 Last updated: Mar 04, 2023	Comment: Reported in an individual with episodic ataxia type 2 (Eunson et al., 2005; Tomlinson et al., 2016); Canonical splice site variant predicted to result in … (more) Reported in an individual with episodic ataxia type 2 (Eunson et al., 2005; Tomlinson et al., 2016); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16043807, 26912519) (less)
Pathogenic (Feb 16, 2023)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000841268.2 First in ClinVar: Oct 20, 2018 Last updated: Jan 26, 2024	Publications: PubMed (5) PubMed: 16043807‚ 26912519‚ 36530930‚ 31506931‚ 33144682 Comment: This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population … (more) This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with episodic ataxia. (less)
Likely pathogenic (Nov 02, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	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	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004571384.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (6) PubMed: 16199547‚ 10371528‚ 19486177‚ 25735478‚ 27250579‚ 16043807 Comment: This sequence change affects a donor splice site in intron 21 of the CACNA1A gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more) This sequence change affects a donor splice site in intron 21 of the CACNA1A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CACNA1A are known to be pathogenic (PMID: 10371528, 19486177, 25735478, 27250579). This variant is present in population databases (no rsID available, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with episodic ataxia (PMID: 16043807). This variant is also known as c.3977+1G>A or c.3704+1G>A. ClinVar contains an entry for this variant (Variation ID: 585567). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Likely pathogenic (Dec 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002063742.19 First in ClinVar: Jan 29, 2022 Last updated: Oct 08, 2024	Number of individuals with the variant: 1
Likely pathogenic (Aug 14, 2020)	no assertion criteria provided Method: clinical testing	Developmental and epileptic encephalopathy, 42 Affected status: yes Allele origin: de novo	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine Accession: SCV001442987.1 First in ClinVar: Nov 14, 2020 Last updated: Nov 14, 2020	Sex: male
not provided (-)	no classification provided Method: phenotyping only	Developmental and epileptic encephalopathy, 42 Spinocerebellar ataxia type 6 Migraine, familial hemiplegic, 1 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: yes Allele origin: maternal	GenomeConnect - Brain Gene Registry Accession: SCV004176866.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: Variant classified as Likely pathogenic and reported on 08-27-2019 by Baylor Genetics. Assertions are reported exactly as they appear on the patient provided laboratory report. … (more) Variant classified as Likely pathogenic and reported on 08-27-2019 by Baylor Genetics. 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 the amniotic fluid (present) , Decreased fetal movement (present) , Abnormal delivery (present) , Pregnancy history (present) , Abnormal placenta morphology (present) , … (more) Abnormality of the amniotic fluid (present) , Decreased fetal movement (present) , Abnormal delivery (present) , Pregnancy history (present) , Abnormal placenta morphology (present) , Maternal teratogenic exposure (present) , Premature birth (present) , Abnormality of the umbilical cord (present) , Overgrowth (present) , Obesity (present) , Hemihypertrophy (present) , Short stature (present) , Failure to thrive (present) , Decreased response to growth hormone stimulation test (present) , Elevated circulating growth hormone concentration (present) , Tall stature (present) , Type 2 diabetes mellitus (present) , Diabetes mellitus type 1 (present) , Delayed puberty (present) , Diabetes insipidus (present) , Precocious puberty (present) , Hypogonadism (present) , Adrenal hyperplasia (present) , Goiter (present) , Hyperthyroidism (present) , Abnormality of the parathyroid physiology (present) , Breast carcinoma (present) , Ovarian neoplasm (present) , Neoplasm of uterus (present) , Cervical cancer (present) , Prostate neoplasm (present) , Neoplasm of lung (present) , Colon cancer (present) , Neoplasm of the pancreas (present) , Bladder neoplasm (present) , Renal neoplasm (present) , Thyroid tumor (present) , Melanoma (present) , Neoplasm of the skin (present) , Neoplasm of the central nervous system (present) , Abnormality of blood and blood-forming tissues (present) , Abnormality of the chin (present) , Orofacial cleft (present) , Abnormal facial shape (present) , Abnormal hair morphology (present) , Abnormal oral cavity morphology (present) , Abnormality of the mouth (present) , Abnormality of the neck (present) , Abnormality of the nose (present) , Abnormal skull morphology (present) , Oral-pharyngeal dysphagia (present) , Abnormality of eye movement (present) , Abnormality of globe size (present) , Abnormality iris morphology (present) , Congenital ocular coloboma (present) , Abnormal lens morphology (present) , Abnormality of vision (present) , Myopia (present) , Hypermetropia (present) , Abnormal optic nerve morphology (present) , Abnormal retinal morphology (present) , Ptosis (present) , Ear malformation (present) , Conductive hearing impairment (present) , Sensorineural hearing loss disorder (present) , Mixed hearing impairment (present) , Hearing impairment (present) , Tinnitus (present) , Hyperacusis (present) , Vertigo (present) , Abnormality of the nervous system (present) , Cerebral palsy (present) , Cognitive impairment (present) , Abnormality of coordination (present) , EEG abnormality (present) , Encephalopathy (present) , Hypertonia (present) , Generalized hypotonia (present) , Memory impairment (present) , Movement disorder (present) , Parkinsonian disorder (present) , Seizure (present) , Autistic behavior (present) , Anxiety (present) , Short attention span (present) , Asthma (present) , Abnormality of the respiratory system (present) , Feeding difficulties (present) , Abnormal esophagus morphology (present) , Abnormal stomach morphology (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: female Method: Exome Sequencing Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2019-08-27 Testing laboratory interpretation: Likely pathogenic
Uncertain significance (Jan 01, 2016)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Migraine, familial hemiplegic, 1 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368671.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PVS1.
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

Reported in an individual with episodic ataxia type 2 (Eunson et al., 2005; Tomlinson et al., 2016); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16043807, 26912519)

Comment:

This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with episodic ataxia.

Comment:

This sequence change affects a donor splice site in intron 21 of the CACNA1A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CACNA1A are known to be pathogenic (PMID: 10371528, 19486177, 25735478, 27250579). This variant is present in population databases (no rsID available, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with episodic ataxia (PMID: 16043807). This variant is also known as c.3977+1G>A or c.3704+1G>A. ClinVar contains an entry for this variant (Variation ID: 585567). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

Variant classified as Likely pathogenic and reported on 08-27-2019 by Baylor Genetics. 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/.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Diagnostic Efficacy of Genetic Studies in a Series of Hereditary Cerebellar Ataxias in Eastern Spain.	Baviera-Muñoz R	Neurology. Genetics	2022	PMID: 36530930
Impact of integrated translational research on clinical exome sequencing.	Klee EW	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 33144682
Variant filtering, digenic variants, and other challenges in clinical sequencing: a lesson from fibrillinopathies.	Najafi A	Clinical genetics	2020	PMID: 31506931
Biallelic CACNA1A mutations cause early onset epileptic encephalopathy with progressive cerebral, cerebellar, and optic nerve atrophy.	Reinson K	American journal of medical genetics. Part A	2016	PMID: 27250579
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
CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms.	Damaj L	European journal of human genetics : EJHG	2015	PMID: 25735478
CACNA1A nonsense mutation is associated with basilar-type migraine and episodic ataxia type 2.	Robbins MS	Headache	2009	PMID: 19486177
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
New calcium channel mutations predict aberrant RNA splicing in episodic ataxia.	Eunson LH	Neurology	2005	PMID: 16043807
High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2.	Denier C	Neurology	1999	PMID: 10371528

Text-mined citations for rs1315533129 ...

These 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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_001127222.2(CACNA1A):c.3692+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1315533129 ...