ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.4225C>T (p.Arg1409Ter)

gnomAD frequency: 0.00001  dbSNP: rs587784376
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000147427 SCV000194834 pathogenic not provided 2013-12-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001057643 SCV001222146 pathogenic RYR1-related disorder 2023-11-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1409*) 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 central core disease (PMID: 30611313). ClinVar contains an entry for this variant (Variation ID: 159849). For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health RCV003998164 SCV004820834 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-10-02 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 29 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, although it has been reported in other phenotype(s) (PMID: 30611313, 33176865). This variant has been identified in 1/249982 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) (clinicalgenome.org). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.

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