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

dbSNP: rs1428157373

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	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.