ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.1948+1G>A

gnomAD frequency: 0.00002  dbSNP: rs745712829
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000455181 SCV000538560 uncertain significance not specified 2016-10-20 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: LOF not established disease mechanism for MH
Labcorp Genetics (formerly Invitae), Labcorp RCV001218682 SCV001390577 likely pathogenic Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5 2023-05-22 criteria provided, single submitter clinical testing 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. ClinVar contains an entry for this variant (Variation ID: 402472). This sequence change affects a donor splice site in intron 13 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 (rs745712829, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with CACNA1S-related conditions.
All of Us Research Program, National Institutes of Health RCV004000600 SCV004830314 uncertain significance Malignant hyperthermia, susceptibility to, 5 2023-10-06 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the +1 position of intron 13 of the CACNA1S gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CACNA1S-related disorders in the literature. This variant has been identified in 5/251466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CACNA1S function due to truncation and splice variants is not an established disease mechanism for autosomal dominant malignant hyperthermia, although it is associated with other phenotype(s) (ClinVar variation ID: 402472). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
Gharavi Laboratory, Columbia University RCV000782247 SCV000920737 uncertain significance not provided 2018-09-16 no assertion criteria provided research

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