Submissions for variant NM_000069.3(CACNA1S):c.2063+1G>A

dbSNP: rs1407484817

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002034158	SCV002317420	likely pathogenic	Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5	2021-02-11	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, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with CACNA1S-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 14 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	RCV003491021	SCV004238518	likely pathogenic	not provided	2023-06-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004011170	SCV004825326	uncertain significance	Malignant hyperthermia, susceptibility to, 5	2023-10-02	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 14 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 CACNA1S-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CACNA1S gene function due to haploinsufficiency is not an established disease mechanism for autosomal dominant malignant hyperthermia, although it is associated with other phenotype(s) (ClinVar Variation ID: 1521923). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.