ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.2029C>T (p.Gln677Ter)

dbSNP: rs878854365
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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 RCV000550931 SCV000659878 pathogenic RYR1-related disorder 2023-01-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln677*) 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: 20583297, 20839240, 23919265, 28818389). 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 congenital muscular dystrophy (PMID: 27854218). ClinVar contains an entry for this variant (Variation ID: 242414). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV001782728 SCV002019940 pathogenic not provided 2020-06-24 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005003587 SCV002780224 pathogenic Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; King Denborough syndrome 2024-06-19 criteria provided, single submitter clinical testing
GeneDx RCV001782728 SCV005201363 pathogenic not provided 2023-12-21 criteria provided, single submitter clinical testing Observed with another RYR1 variant in an individual with congenital muscular dystrophy in published literature (PMID: 27854218); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27854218)
PreventionGenetics, part of Exact Sciences RCV000550931 SCV004118588 pathogenic RYR1-related disorder 2024-01-31 no assertion criteria provided clinical testing The RYR1 c.2029C>T variant is predicted to result in premature protein termination (p.Gln677*). This variant, along with a missense variant in RYR1, were reported in the compound heterozygous state in an individual with congenital muscular dystrophy (#11, Punetha et al. 2016. PubMed ID: 27854218). This variant is reported in one allele out of ~251,000 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 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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