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

dbSNP: rs1315533129

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000710953	SCV000841268	pathogenic	not provided	2023-02-16	criteria provided, single submitter	clinical testing	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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000710953	SCV001447018	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001328546	SCV001519690	likely pathogenic	Episodic ataxia type 2	2019-08-27	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
CeGaT Center for Human Genetics Tuebingen	RCV000710953	SCV002063742	likely pathogenic	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000710953	SCV002064441	likely pathogenic	not provided	2018-02-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000710953	SCV002102761	pathogenic	not provided	2022-02-24	criteria provided, single submitter	clinical testing	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)
Invitae	RCV003768098	SCV004571384	likely pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2023-11-02	criteria provided, single submitter	clinical testing	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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197888	SCV001368671	uncertain significance	Migraine, familial hemiplegic, 1	2016-01-01	flagged submission	clinical testing	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PVS1.
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV001264752	SCV001442987	likely pathogenic	Developmental and epileptic encephalopathy, 42	2020-08-14	no assertion criteria provided	clinical testing
GenomeConnect - Brain Gene Registry	RCV003458325	SCV004176866	not provided	Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 42		no assertion provided	phenotyping only	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/.