ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.1233-1G>A

gnomAD frequency: 0.00001  dbSNP: rs760082356
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002022552 SCV002295913 likely pathogenic Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5 2023-11-15 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 9 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 (rs760082356, gnomAD 0.002%). 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: 1502887). 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.
Johns Hopkins Genomics, Johns Hopkins University RCV002282680 SCV002570404 likely pathogenic Hypokalemic periodic paralysis, type 1 2022-06-20 criteria provided, single submitter clinical testing This CACNA1S variant (rs760082356) is rare (<0.1%) in a large population dataset (gnomAD: 2/251438 total alleles; 0.0008%; no homozygotes) and has been reported in ClinVar. Bioinformatic analysis predicts that this variant would disrupt the canonical splice acceptor site for exon 10 although this has not been confirmed experimentally to our knowledge. This variant has not been reported in the literature in individuals affected with MHS5. We consider c.1233-1G>A to be likely pathogenic.
Genome-Nilou Lab RCV003446985 SCV004173628 likely pathogenic Malignant hyperthermia, susceptibility to, 5 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002282680 SCV004173629 likely pathogenic Hypokalemic periodic paralysis, type 1 2023-04-11 criteria provided, single submitter clinical testing

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