Submissions for variant NM_000540.3(RYR1):c.12063_12064dup (p.Met4022fs)

dbSNP: rs1419938249

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000721258	SCV000852279	likely pathogenic	not provided	2015-09-17	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV002225115	SCV002503796	pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change is a duplication of 2 bp in exon 88 (of 106) of RYR1 that is predicted to create a premature termination codon at position 4025, p.(Met4022Thrfs*4). It is expected to result in nonsense-mediated decay in a gene where loss of function is a mechanism of disease in recessive RYR1-related disorders. The variant is present in a large population cohort at a frequency of 0.001%, which is consistent with recessive disease (rs1419938249, 3/251,476 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified with a second RYR1 allele in at least four individuals with a diagnosis of congenital myopathy (PMID: 25957634, 30155738; LOVD Individual #00218031, #00218030). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_Strong, PM2.
Fulgent Genetics, Fulgent Genetics	RCV002507263	SCV002809803	pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-09-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002534997	SCV003443238	pathogenic	RYR1-related disorder	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met4022Thrfs*4) 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 0.003%). This premature translational stop signal has been observed in individual(s) with autosomal recessive RYR1-related myopathy (PMID: 23919265, 25957634, 28269792). ClinVar contains an entry for this variant (Variation ID: 590394). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000721258	SCV003914959	pathogenic	not provided	2022-10-06	criteria provided, single submitter	clinical testing	Frameshift 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: 25957634, 23919265)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004788146	SCV005398828	pathogenic	RYR1-related myopathy	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with RYR1-related disorders. Central core disease (MIM#117000), congenital neuromuscular disease with uniform type 1 fiber (MIM#17000) and minicore myopathy with external ophthalmoplegia (MIM#255320) are associated with loss of function, while a gain of function mechanism has been described in the context of malignant hyperthermia susceptibility (MIM#145600; PMIDs: 27855725, 23919265). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 3 heterozygotes, 0 homozygotes). (SP) 0701 - Other variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with autosomal recessive RYR1-related myopathies with parents reported as unaffected carriers (ClinVar, PMIDs: 30155738, 25957634, 28269792). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign