ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.8463G>A (p.Trp2821Ter)

dbSNP: rs1057518773
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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 RCV001861443 SCV002140425 pathogenic RYR1-related disorder 2021-10-09 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp2821*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 373926). This premature translational stop signal has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 22473935).
PreventionGenetics, part of Exact Sciences RCV001861443 SCV004104223 pathogenic RYR1-related disorder 2023-01-27 criteria provided, single submitter clinical testing The RYR1 c.8463G>A variant is predicted to result in premature protein termination (p.Trp2821*). This variant has been reported in the compound heterozygous state in two individuals with myopathies (Klein et al 2012. PubMed ID: 22473935; Babić Božović I et al 2021. PubMed ID: 34106991). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in RYR1 are expected to be pathogenic for autosomal recessive myopathy phenotypes but not malignant hyperthermia. This variant is interpreted as pathogenic for autosomal recessive myopathy.
Fulgent Genetics, Fulgent Genetics RCV005018713 SCV005647472 pathogenic Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; King Denborough syndrome 2024-03-13 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000415002 SCV000492561 likely pathogenic Myopathy 2016-07-06 no assertion criteria provided clinical testing
All of Us Research Program, National Institutes of Health RCV003995931 SCV004821024 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-01-10 flagged submission clinical testing This pathogenicity assessment is for autosomal dominant malignant hyperthermia susceptibility phenotype. This frameshift variant is predicted to result in an absent RYR1 protein product. Loss of RYR1 function due to haploinsufficiency is associated with congenital myopathy (https://clinicalgenome.org/), but it is not an established disease mechanism for autosomal dominant malignant hyperthermia susceptibility. Therefore, this variant is classified as a Variant of Uncertain Significance for malignant hyperthermia susceptibility.

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