Submissions for variant NM_000540.3(RYR1):c.11763C>A (p.Tyr3921Ter)

gnomAD frequency: 0.00004  dbSNP: rs377178986

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704053	SCV000832986	pathogenic	RYR1-related disorder	2024-08-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr3921*) 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 (rs377178986, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with autosomal recessive RYR1-related conditions (PMID: 22473935, 28818389). ClinVar contains an entry for this variant (Variation ID: 161361). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000721251	SCV000852268	pathogenic	not provided	2019-10-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478416	SCV000894193	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	2022-04-11	criteria provided, single submitter	clinical testing
Mendelics	RCV000990206	SCV001141073	pathogenic	Malignant hyperthermia, susceptibility to, 1	2022-05-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001266922	SCV001445103	pathogenic	Inborn genetic diseases	2024-11-01	criteria provided, single submitter	clinical testing	The c.11763C>A (p.Y3921*) alteration, located in coding exon 85 of the RYR1 gene, consists of a C to A substitution at nucleotide position 11763. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 3921. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Although biallelic loss of function of RYR1 has been associated with autosomal recessive RYR1-related myopathy, haploinsufficiency of RYR1 has not been established as a mechanism of disease for autosomal dominant RYR1-related myopathy and malignant hyperthermia susceptibility. for autosomal recessive RYR1-related myopathy; however, it is unlikely to be causative of autosomal dominant RYR1-related myopathy, and its clinical significance for autosomal dominant malignant hyperthermia susceptibility is uncertain Based on data from gnomAD, the A allele has an overall frequency of 0.003% (8/282888) total alleles studied. The highest observed frequency was 0.008% (2/24966) of African alleles. This alteration has been reported multiple times in trans with non-truncating alterations in patients that present with early-onset RYR1-related myopathy. The clinical severity of these individuals vary from walking with no ocular involvement to severe congenital contractures of the limb and face with ocular, respiratory, and skeletal involvement (Klein, 2012; Chong, 2015; Abath Neto, 2017). Based on the available evidence, this alteration is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001795258	SCV001774653	pathogenic	Congenital myopathy with fiber type disproportion	2021-07-08	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.11763C>A (p.Tyr3921X) results in a premature termination codon, experimentally demonstrated to lead to absence of transcription (and therefore of the protein) (Zhou_2006, Klein_2012) due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 2.4e-05 in 251492 control chromosomes (gnomAD). c.11763C>A has been reported in the literature in individuals affected with autosomal recessive RYR1-related myopathy (e.g. Klein_2012, Amburgey_2013). These data indicate that the variant is likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and one ClinVar submitter (evaluation after 2014) cites it as benign. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000721251	SCV002019102	likely pathogenic	not provided	2021-11-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000721251	SCV003805531	pathogenic	not provided	2023-02-24	criteria provided, single submitter	clinical testing	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 a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25637381, 28818389, 32721234, 25683120, 22473935, 23553484)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786401	SCV005398256	pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2024-10-08	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 (OMIM). Gain of function mechanism has been described in the context of malignant hyperthermia susceptibility 1 (MIM#145600) and autosomal dominant congenital myopathy 1A with susceptibility to malignant hyperthermia (MIM#117000). Autosomal recessive congenital myopathy 1B (MIM#255320) is associated with a loss of function mechanism (PMIDs: 27855725, 23919265). The mechanism of King-Denborough syndrome (MIM#619542) is unclear. (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 (8 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants 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. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar, and has been observed as compound heterozygous in individuals with autosomal recessive myopathies (PMIDs: 28818389, 22473935, 23919265). This variant has also been classified as a VUS in an infant with respiratory failure and a suspected neurological condition where no second variant was mentioned (PMID: 36757698). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
All of Us Research Program, National Institutes of Health	RCV000990206	SCV005425318	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-09-16	criteria provided, single submitter	clinical testing	This pathogenicity assessment is for autosomal dominant malignant hyperthermia susceptibility phenotype. This variant changes 1 nucleotide in exon 85 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 in the literature. This variant has been identified in 8/282888 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RYR1 function due to truncation variants is associated with congenital myopathy (clinicalgenome.org), but it is not an established disease mechanism for malignant hyperthermia susceptibility. While this particular variant is known to be pathogenic for myopathy (ClinVar variation ID: 161361), the available evidence is insufficient to determine the role of this variant in malignant hyperthermia susceptibility. Therefore, this variant is classified as a Variant of Uncertain Significance.
CSER _CC_NCGL, University of Washington	RCV000148788	SCV000190526	likely benign	Congenital myopathy	2014-06-01	no assertion criteria provided	research