Submissions for variant NM_000540.3(RYR1):c.10946dup (p.Cys3650fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003593338	SCV004297342	pathogenic	RYR1-related disorder	2023-03-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys3650Metfs*2) 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). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with autosomal recessive RYR1-related myopathy (PMID: 28818389). This variant is not present in population databases (gnomAD no frequency).
All of Us Research Program, National Institutes of Health	RCV004011417	SCV004830245	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-06-08	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 75 of the RYR1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has not been identified 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) (https://clinicalgenome.org/). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.