ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.1234C>T (p.Arg412Ter)

gnomAD frequency: 0.00001  dbSNP: rs767052156
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002037707 SCV002233621 pathogenic Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5 2024-12-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg412*) in the CACNA1S gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CACNA1S are known to be pathogenic (PMID: 26247046, 28012042). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CACNA1S-related conditions. ClinVar contains an entry for this variant (Variation ID: 1452647). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002479575 SCV002798583 likely pathogenic Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5; Thyrotoxic periodic paralysis, susceptibility to, 1 2022-05-25 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003453850 SCV004179168 pathogenic Malignant hyperthermia, susceptibility to, 5 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003453849 SCV004179170 pathogenic Hypokalemic periodic paralysis, type 1 2023-04-11 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003453850 SCV004815224 uncertain significance Malignant hyperthermia, susceptibility to, 5 2023-02-24 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 10 of the CACNA1S gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with CACNA1S-related disorders in the literature. This variant has been identified in 2/282624 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CACNA1S gene function due to truncation variants is not an established disease mechanism for autosomal dominant malignant hyperthermia, although it is associated with other phenotype(s) (ClinVar Variation ID: 1452647). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

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