ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.58G>A (p.Val20Ile)

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Total submissions: 2
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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 RCV003988247 SCV004803721 uncertain significance not specified 2024-01-03 criteria provided, single submitter clinical testing Variant summary: RYR1 c.58G>A (p.Val20Ile) results in a conservative amino acid change located in the Inositol 1,4,5-trisphosphate/ryanodine receptor domain (IPR014821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 240326 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.58G>A in individuals affected with Myopathy, RYR1-Associated and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health RCV004006194 SCV004818596 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-03-23 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 20 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 RYR1-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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