ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.4798-2A>G

dbSNP: rs1428157373
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000792372 SCV000931666 likely pathogenic Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5 2023-08-14 criteria provided, single submitter clinical testing 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. 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: 639552). This variant has not been reported in the literature in individuals affected with CACNA1S-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change affects an acceptor splice site in intron 39 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).
Revvity Omics, Revvity RCV002473138 SCV002025041 likely pathogenic not provided 2021-06-24 criteria provided, single submitter clinical testing
GeneDx RCV002473138 SCV002770376 likely pathogenic not provided 2022-06-21 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; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab RCV003446434 SCV004172989 likely pathogenic Malignant hyperthermia, susceptibility to, 5 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001784407 SCV004172990 likely pathogenic Hypokalemic periodic paralysis, type 1 2023-04-11 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003446434 SCV004833325 uncertain significance Malignant hyperthermia, susceptibility to, 5 2023-07-10 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the -2 position of intron 39 of the CACNA1S gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with malignant hyperthermia susceptibility in the literature but may be associated with other condition(s) (ClinVar variation ID: 639552). This variant has been identified in 1/249854 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CACNA1S function due to haploinsufficiency is not an established disease mechanism for autosomal dominant malignant hyperthermia susceptibility. Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

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