Submissions for variant NM_000540.3(RYR1):c.10171G>T (p.Glu3391Ter)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen	RCV004738750	SCV005367849	likely pathogenic	RYR1-related myopathy	2024-09-09	reviewed by expert panel	curation	The NM_000540.3(RYR1):c.10171G>T (p.Glu3391Ter) variant in RYR1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 67/106 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000004243 (5/1178340 alleles) in European (non-Finnish) population, which is lower than the ClinGen Congenital Myopathies VCEP threshold (≤0.00000697) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PM2_P. (Required: ClinGen Congenital Myopathies VCEP specifications version 1; September 9, 2024)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003592670	SCV004260234	pathogenic	RYR1-related disorder	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu3391*) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV004011356	SCV004820974	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-04-28	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 67 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 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 haploinsufficiency 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.