ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.7064G>A (p.Arg2355Gln)

gnomAD frequency: 0.00004  dbSNP: rs144526634
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001066687 SCV001231703 uncertain significance RYR1-related disorder 2023-10-04 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2355 of the RYR1 protein (p.Arg2355Gln). This variant is present in population databases (rs144526634, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 860398). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. This variant disrupts the p.Arg2355 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15210166, 19648156, 23558838, 24361844). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Fulgent Genetics, Fulgent Genetics RCV002482105 SCV002788847 uncertain significance Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome 2022-05-04 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004000162 SCV004820898 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-09-04 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 2355 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 been identified in 3/270886 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Arg2355Trp, is associated with malignant hyperthermia susceptibility (ClinVar variation ID: 133183). Due to the lack of variant-specific data, the available evidence is insufficient to determine the role of p.Arg2355Gln variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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