ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.2055G>C (p.Lys685Asn)

gnomAD frequency: 0.00003  dbSNP: rs200844059
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001042522 SCV001206205 benign Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5 2023-07-18 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002481896 SCV002781459 uncertain significance Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5; Thyrotoxic periodic paralysis, susceptibility to, 1 2021-10-15 criteria provided, single submitter clinical testing
GeneDx RCV002508281 SCV002817803 uncertain significance not provided 2022-06-28 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003490022 SCV004241020 uncertain significance not specified 2023-12-13 criteria provided, single submitter clinical testing Variant summary: CACNA1S c.2055G>C (p.Lys685Asn) results in a non-conservative amino acid change in 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 1.2e-05 in 250774 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2055G>C in individuals affected with Hypokalemic Periodic Paralysis and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) or benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health RCV004004750 SCV004820997 uncertain significance Malignant hyperthermia, susceptibility to, 5 2023-08-15 criteria provided, single submitter clinical testing This missense variant replaces lysine with asparagine at codon 685 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 4/282180 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.
Mayo Clinic Laboratories, Mayo Clinic RCV002508281 SCV005408533 uncertain significance not provided 2023-12-07 criteria provided, single submitter clinical testing

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