Submissions for variant NM_000540.3(RYR1):c.13013_13032del (p.Ala4338fs)

dbSNP: rs193922856

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen	RCV004737151	SCV005367855	pathogenic	RYR1-related myopathy	2024-08-07	reviewed by expert panel	curation	The NM_000540.3:c.13013_13032del p.(Ala4338Glyfs*238) variant in RYR1 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 91/106 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 is 0.000004965 (5/1006982 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Congenital Myopathies VCEP threshold (≤ 0.00000697) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant was found in trans with an RYR1 VUS NM_000540.3:c.1559T>C p.(Leu520Pro), in an adult woman affected with centronuclear myopathy which is highly compatible with recessive RYR1-related myopathy (PM3_Supporting, PP4, Internal VCEP contributors). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PM2_Supporting, PM3_Supporting, PP4 (Congenital Myopathies VCEP specifications Version 1: 8/7/2024)
PreventionGenetics, part of Exact Sciences	RCV000119472	SCV000852331	pathogenic	not provided	2015-08-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000119472	SCV001246309	pathogenic	not provided	2017-03-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001216605	SCV001388409	pathogenic	RYR1-related disorder	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala4338Glyfs*238) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive congenital fiber-type disproportion and/or congenital neuromuscular disease with uniform type 1 fiber (PMID: 17538032; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12996). For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV002288489	SCV002580750	pathogenic	Central core myopathy	2022-02-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000119472	SCV004036863	likely pathogenic	not provided	2023-09-16	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 701 amino acids are replaced with 237 different amino acids, and other loss-of-function variants have been reported downstream in the published literature (Sato et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33184643, 34595679, 17538032)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004737151	SCV005399211	pathogenic	RYR1-related myopathy	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, 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 myopathy. Central core disease and minicore myopathy are associated with loss of function, while a gain of function mechanism has been described in the context of malignant hyperthermia susceptibility (PMID: 27855725). (I) 0108 - This gene is associated with both recessive and dominant disease. Autosomal dominant inheritance is associated with central core disease ((MIM#117000) or susceptibility to malignant hyperthermia (MIM#145600). Other phenotypes include minicore myopathy (MIM#255320) which is associated with autosomal recessive inheritance (PMID: 23919265) and neuromuscular disease, congenital, with uniform type 1 fiber (MIM#117000) which is associated with both autosomal dominant and recessive inheritance (OMIM). (I) 0113 - This gene is suspected to be imprinted and paternally expressed (OMIM; PMID: 17033962). (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) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are at least 10 NMD-predicted variants along the RYR1 gene (Decipher). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified pathogenic in three individuals in ClinVar and shown to be de novo in one individual with congenital neuromuscular disease with uniform type 1 fiber (Clinvar; PMID: 17538032). (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
OMIM	RCV000013870	SCV000034117	pathogenic	Neuromuscular disease, congenital, with uniform type 1 fiber	2008-01-08	no assertion criteria provided	literature only
Leiden Muscular Dystrophy (RYR1)	RCV000119472	SCV000154379	not provided	not provided		no assertion provided	not provided