ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.839G>A (p.Arg280Gln)

gnomAD frequency: 0.00001  dbSNP: rs1319877486
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001068410 SCV001233522 uncertain significance RYR1-related disorder 2021-08-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 280 of the RYR1 protein (p.Arg280Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Pediatric Department, Peking University First Hospital RCV001827449 SCV002097050 likely pathogenic Congenital multicore myopathy with external ophthalmoplegia 2022-02-08 criteria provided, single submitter provider interpretation
All of Us Research Program, National Institutes of Health RCV004000176 SCV004820725 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-09-23 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 280 of the RYR1 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 autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar Variation ID: 861815). This variant has been identified in 1/249082 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

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