ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.3774G>C (p.Trp1258Cys)

dbSNP: rs1660729185
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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 RCV001067800 SCV001232880 uncertain significance Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5 2019-05-08 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with CACNA1S-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with cysteine at codon 1258 of the CACNA1S protein (p.Trp1258Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine.
All of Us Research Program, National Institutes of Health RCV004000170 SCV004828921 uncertain significance Malignant hyperthermia, susceptibility to, 5 2023-06-08 criteria provided, single submitter clinical testing This missense variant replaces tryptophan with cysteine at codon 1258 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 not been identified 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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