Submissions for variant NM_000540.3(RYR1):c.7858C>T (p.Gln2620Ter)

gnomAD frequency: 0.00001  dbSNP: rs1365856881

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001219907	SCV001391872	pathogenic	RYR1-related disorder	2024-09-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln2620*) 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 multi-minicore disease (PMID: 25960145; internal data). ClinVar contains an entry for this variant (Variation ID: 948615). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001780144	SCV002019951	pathogenic	not provided	2019-09-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005005088	SCV002785808	pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; King Denborough syndrome	2024-06-04	criteria provided, single submitter	clinical testing
GeneDx	RCV001780144	SCV005325374	likely pathogenic	not provided	2024-02-07	criteria provided, single submitter	clinical testing	Reported in published literature in a patient with multiminicore disease who also harbored the R3539H variant in RYR1, which is classified as likely benign by GeneDx; familial segregation analysis was not performed (PMID: 25960145); 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: 25960145)
All of Us Research Program, National Institutes of Health	RCV004803576	SCV005425111	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-08-30	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 49 of the RYR1 gene, creating a 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 malignant hyperthermia susceptibility. This variant has been identified in 1/249786 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 phenotypes (ClinVar Variation ID: 948615, PMID: 25960145). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University	RCV003156321	SCV002576303	likely pathogenic	Central core myopathy		no assertion criteria provided	provider interpretation