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

dbSNP: rs146497999

Total submissions: 8

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
All of Us Research Program, National Institutes of Health	RCV002221220	SCV004818232	uncertain significance	Malignant hyperthermia, susceptibility to, 5	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 993 of the CACNA1S protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with malignant hyperthermia in the literature. This variant has been identified in 3/251280 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004021408	SCV004915031	uncertain significance	Inborn genetic diseases	2024-02-21	criteria provided, single submitter	clinical testing	The c.2979C>A (p.S993R) alteration is located in exon 24 (coding exon 24) of the CACNA1S gene. This alteration results from a C to A substitution at nucleotide position 2979, causing the serine (S) at amino acid position 993 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.