ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.1949-8_1986del

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003795347 SCV004579177 likely pathogenic Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5 2022-10-23 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. 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 0.007%). This variant results in the deletion of part of exon 14 (c.1949-8_1986del) 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).
All of Us Research Program, National Institutes of Health RCV004006009 SCV004819878 uncertain significance Malignant hyperthermia, susceptibility to, 5 2023-04-03 criteria provided, single submitter clinical testing This variant causes the deletion of 46 nucleotides in exon 14 and intron 13 of the CACNA1S gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been reported in individuals affected with CACNA1S-related disorders in the literature. This variant has been identified in 1/31394 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, although it has been associated with other phenotypes (PMID: 28012042, 34608571, 34777470). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

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