Submissions for variant NM_000540.3(RYR1):c.14833C>T (p.Arg4945Ter)

gnomAD frequency: 0.00001  dbSNP: rs1432807966

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541517	SCV000659860	pathogenic	RYR1-related disorder	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg4945*) 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 autosomal recessive congenital myopathy (PMID: 29172004). This variant has been reported in individual(s) with autosomal dominant malignant hyperthermia susceptibility (PMID: 24433488); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 478201). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000595499	SCV000705505	likely pathogenic	not provided	2017-02-22	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000595499	SCV001450334	likely pathogenic	not provided	2017-01-03	criteria provided, single submitter	clinical testing
3billion	RCV002250657	SCV002521719	pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000478201 / PMID: 29172004). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV002497202	SCV002810516	likely pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-10-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999490	SCV004816276	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-08-28	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 103 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 been reported in one individual with autosomal dominant malignant hyperthermia (PMID: 24433488), and has been observed in individuals with other phenotype(s) (PMID: 29172004). This variant has been identified in 1/31344 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) (ClinVar variation ID: 478201). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.