ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.1983G>A (p.Trp661Ter)

gnomAD frequency: 0.00001  dbSNP: rs1305971341
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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 RCV001058792 SCV001223387 pathogenic RYR1-related disorder 2024-01-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp661*) 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). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive congenital myopathy (PMID: 21911697). ClinVar contains an entry for this variant (Variation ID: 853883). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV001784614 SCV002019955 pathogenic not provided 2021-05-12 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002505620 SCV002803709 pathogenic Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome 2021-10-08 criteria provided, single submitter clinical testing
GeneDx RCV001784614 SCV004028116 likely pathogenic not provided 2023-08-11 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Identified in an individual with congenital myopathy who had a likely pathogenic RYR1 variant on the opposite allele (in trans) (Klein et al., 2011; Klein et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22473935, 23127960, 31903994, 21911697)
All of Us Research Program, National Institutes of Health RCV004000105 SCV004820760 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-12-18 flagged submission clinical testing This variant changes 1 nucleotide in exon 18 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 been identified in 2/282590 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RYR1 function due to haploinsufficiency is not an established disease mechanism for autosomal dominant malignant hyperthermia, although it is associated with other phenotype(s) (ClinVar Variation ID: 853883). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

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