ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.157T>C (p.Phe53Leu)

dbSNP: rs754668127
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002004642 SCV002230407 uncertain significance Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 53 of the CACNA1S protein (p.Phe53Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs754668127, ExAC 0.001%). This variant has not been reported in the literature in individuals affected with CACNA1S-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1S protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health RCV004010979 SCV004820490 uncertain significance Malignant hyperthermia, susceptibility to, 5 2023-04-03 criteria provided, single submitter clinical testing This missense variant replaces phenylalanine with leucine at codon 53 of the CACNA1S protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 1/251434 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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