ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.1369C>T (p.Pro457Ser)

gnomAD frequency: 0.00001  dbSNP: rs372374492
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482187 SCV000573431 uncertain significance not provided 2017-02-28 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA1S gene. The P457S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P457S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P457S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with CACNA1S-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001212349 SCV001383932 benign Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5 2022-08-31 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002475950 SCV002789591 uncertain significance Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5; Thyrotoxic periodic paralysis, susceptibility to, 1 2022-05-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV002526955 SCV003632977 uncertain significance Inborn genetic diseases 2022-07-19 criteria provided, single submitter clinical testing The c.1369C>T (p.P457S) alteration is located in exon 10 (coding exon 10) of the CACNA1S gene. This alteration results from a C to T substitution at nucleotide position 1369, causing the proline (P) at amino acid position 457 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV004003404 SCV004828370 uncertain significance Malignant hyperthermia, susceptibility to, 5 2024-01-11 criteria provided, single submitter clinical testing This missense variant replaces proline with serine at codon 457 of the CACNA1S protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CACNA1S-related disorders in the literature. This variant has been identified in 1/251368 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.

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