Submissions for variant NM_001127222.2(CACNA1A):c.631+5G>A

dbSNP: rs786200963

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000996802	SCV001151730	uncertain significance	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Invitae	RCV001052102	SCV001216295	uncertain significance	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2022-11-08	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 187829). This variant has been observed in individual(s) with episodic ataxia (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 4 of the CACNA1A gene. It does not directly change the encoded amino acid sequence of the CACNA1A protein. It affects a nucleotide within the consensus splice site.
Illumina Laboratory Services, Illumina	RCV003985284	SCV001786599	likely pathogenic	CACNA1A-related disorder	2021-03-31	criteria provided, single submitter	clinical testing	The CACNA1A c.631+5G>A variant, also referred to as c.868+5G>A in the literature, is a splice region variant that has been reported in one study, in which it was identified in a proband with episodic ataxia type 2 and in his affected mother (Damaj et al. 2015). Another variant at the same nucleotide position has also been reported in two individuals with CACNA1A-related disorders (Gur-Hartman et al. 2021). The c.631+5G>A variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence, the c.631+5G>A variant is classified as likely pathogenic for CACNA1A-related disorders.
Athena Diagnostics Inc	RCV000996802	SCV001879663	uncertain significance	not provided	2021-11-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000996802	SCV004021822	likely pathogenic	not provided	2023-07-12	criteria provided, single submitter	clinical testing	Intronic variant directly or indirectly altering the +5 splice site in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37177896, 25735478, 33349592)
E. Rossignol Lab, CHU Ste-Justine, Universite de Montreal	RCV000169641	SCV000196751	likely pathogenic	Episodic ataxia type 2	2014-11-25	no assertion criteria provided	clinical testing