ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.838C>T (p.Arg280Ter)

gnomAD frequency: 0.00001  dbSNP: rs1278804520
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000760976 SCV000890881 pathogenic Central core myopathy 2017-08-29 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003757205 SCV004525384 pathogenic RYR1-related disorder 2024-02-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg280*) in the RYR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RYR1 are known to be pathogenic (PMID: 23919265, 25960145, 28818389, 30611313). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with RYR1-related conditions (PMID: 29556213). ClinVar contains an entry for this variant (Variation ID: 620584). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences RCV003757205 SCV005362192 pathogenic RYR1-related disorder 2024-04-16 no assertion criteria provided clinical testing The RYR1 c.838C>T variant is predicted to result in premature protein termination (p.Arg280*). This variant, along with a missense variant in RYR1, were reported in an individual with congenital myopathy (Table 2, Todd et al. 2018. PubMed ID: 29556213). This variant is reported in two alleles out of ~280,000 alleles in the gnomAD database. Loss of function variants, including frameshift, splicing, and nonsense variants have only been observed for the autosomal recessive myopathy phenotype and are expected to be pathogenic for this phenotype. Loss of function variants are not established as causative for autosomal dominant malignant hyperthermia. Taken together, this variant is interpreted as pathogenic for autosomal recessive RYR1-related disorders and interpreted as uncertain for autosomal dominant malignant hyperthermia.

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