ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.2632G>A (p.Val878Met)

gnomAD frequency: 0.00004  dbSNP: rs202131129
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780079 SCV000917103 uncertain significance not specified 2018-06-14 criteria provided, single submitter clinical testing Variant summary: CACNA1S c.2632G>A (p.Val878Met) results in a conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 277096 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.2632G>A, has been reported in the literature in individuals affected with SCN1A-positive Dravet Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Hypokalemic Periodic Paralysis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx RCV001766618 SCV002008960 uncertain significance not provided 2021-02-04 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in the literature in an individual with Dravet Syndrome who was positive for an SCN1A variant and variants in other neuronal-associated genes (Hammer et al., 2017); This variant is associated with the following publications: (PMID: 28686619)
Labcorp Genetics (formerly Invitae), Labcorp RCV001856184 SCV002157306 likely benign Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5 2024-10-22 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004001512 SCV004817445 uncertain significance Malignant hyperthermia, susceptibility to, 5 2024-09-23 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 878 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, but has been reported in one individual with SCN1A-related Dravet syndrome (PMID: 28686619). This variant has been identified in 5/282722 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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