ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.2365C>T (p.Arg789Cys)

gnomAD frequency: 0.00001  dbSNP: rs148895719
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000427648 SCV000531689 uncertain significance not provided 2019-07-24 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016) In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV000807013 SCV000947038 uncertain significance Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 789 of the CACNA1S protein (p.Arg789Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with CACNA1S-related disease. ClinVar contains an entry for this variant (Variation ID: 389230). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003387844 SCV004100204 uncertain significance not specified 2023-09-27 criteria provided, single submitter clinical testing Variant summary: CACNA1S c.2365C>T (p.Arg789Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 157372 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2365C>T has been reported in the literature in at least one compound heterozygous individual with clinical features of autosomal recessive congenital myopathy 18 (e.g., Ravenscroft_2021). However, this data does not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33060286). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; two submitters classified it as a variant of uncertain significance, while one classified it as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab RCV003456069 SCV004177900 uncertain significance Malignant hyperthermia, susceptibility to, 5 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003456070 SCV004177901 uncertain significance Thyrotoxic periodic paralysis, susceptibility to, 1 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003221977 SCV004177902 uncertain significance Congenital myopathy 18 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003449073 SCV004177904 uncertain significance Hypokalemic periodic paralysis, type 1 2023-04-11 criteria provided, single submitter clinical testing
OMIM RCV003221977 SCV003841110 pathogenic Congenital myopathy 18 2023-03-10 no assertion criteria provided literature only

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