ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.2984G>A (p.Trp995Ter)

dbSNP: rs1440262870
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000811818 SCV000952105 pathogenic RYR1-related disorder 2019-07-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp995*) in the RYR1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with other RYR1 variants in an individual affected with RYR1-related myopathy (PMID: 30611313). Loss-of-function variants in RYR1 are known to be pathogenic (PMID: 20583297, 20839240, 23919265, 28818389). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002495127 SCV002782726 likely pathogenic Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome 2022-01-10 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003141824 SCV003827249 pathogenic not provided 2021-12-19 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV003141824 SCV005878502 likely pathogenic not provided 2023-12-21 criteria provided, single submitter clinical testing The RYR1 c.2984G>A; p.Trp995Ter variant (rs1440262870, ClinVar Variation ID: 655606), is reported in the literature in the compound heterozygous state in an individual with a mild form of myopathy (Garibaldi 2019). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be likely pathogenic. References: Garibaldi M et al. 'Dusty core disease' (DuCD): expanding morphological spectrum of RYR1 recessive myopathies. Acta Neuropathol Commun. 2019 Jan 5;7(1):3. PMID: 30611313.
All of Us Research Program, National Institutes of Health RCV004001735 SCV004820794 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-02-05 flagged submission clinical testing This variant changes 1 nucleotide in exon 24 of the RYR1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature. This variant has been identified in 1/249272 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RYR1 function due to truncation variants is not an established disease mechanism for autosomal dominant malignant hyperthermia, although it is associated with other phenotype(s) (ClinVar Variation ID: 655606). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

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