Submissions for variant NM_000069.3(CACNA1S):c.5049-2A>G

gnomAD frequency: 0.00056  dbSNP: rs148989517

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000651268	SCV000773119	likely pathogenic	Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 40 of the CACNA1S 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 CACNA1S are known to be pathogenic (PMID: 26247046, 28012042). This variant is present in population databases (rs148989517, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with CACNA1S-related conditions. ClinVar contains an entry for this variant (Variation ID: 541072). 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.
Mendelics	RCV002248848	SCV002518633	uncertain significance	Hypokalemic periodic paralysis, type 1	2022-05-30	criteria provided, single submitter	clinical testing
GeneDx	RCV002260656	SCV002540394	likely pathogenic	not provided	2024-10-03	criteria provided, single submitter	clinical testing	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; Has not been previously published as pathogenic or benign in association with CACNA1S-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 30476936)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469236	SCV002766581	uncertain significance	not specified	2022-11-09	criteria provided, single submitter	clinical testing	Variant summary: CACNA1S c.5049-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.8e-05 in 251240 control chromosomes. The observed variant frequency is approximately 70-fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1S causing Hypokalemic Periodic Paralysis phenotype (1.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.5049-2A>G in individuals affected with Hypokalemic Periodic Paralysis and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One classified it as likely pathogenic and two as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.