ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.2979C>A (p.Ser993Arg)

dbSNP: rs146497999
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000290207 SCV000353018 uncertain significance Hypokalemic periodic paralysis, type 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Molecular Genetics, Royal Melbourne Hospital RCV002221220 SCV002498693 uncertain significance Malignant hyperthermia, susceptibility to, 5 2021-08-10 criteria provided, single submitter clinical testing This sequence change in CANA1S is predicted to replace serine with arginine at codon 993 (p.(Ser993Arg)). The serine residue is moderately conserved (100 vertebrates, UCSC), and is located in the extracellular loop of domain III. There is a large physicochemical difference between serine and arginine. The highest population minor allele frequency in gnomAD v2.1 is 0.006% (1/16,246 alleles) in the African/African American population. This variant has been reported as a variant of uncertain significance (ClinVar ID: 294735), and to our knowledge, has not been reported in the literature in any individuals with malignant hyperthermia. Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none.
Genome-Nilou Lab RCV002221220 SCV004177764 uncertain significance Malignant hyperthermia, susceptibility to, 5 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003454890 SCV004177765 uncertain significance Thyrotoxic periodic paralysis, susceptibility to, 1 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003458406 SCV004177766 uncertain significance Congenital myopathy 18 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000290207 SCV004177767 uncertain significance Hypokalemic periodic paralysis, type 1 2023-04-11 criteria provided, single submitter clinical testing

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