Submissions for variant NM_000540.3(RYR1):c.6721C>T (p.Arg2241Ter)

gnomAD frequency: 0.00013  dbSNP: rs200563280

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147436	SCV000194849	pathogenic	not provided	2013-11-05	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000147436	SCV000230536	pathogenic	not provided	2015-02-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000171129	SCV000245532	pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2013-12-23	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant [T4709M] in a 25-year-old female with motor delays, tinnitus, vertigo, central hypotonia, peripheral hypertonia, pes cavus, dysmorphisms, microcephaly, ophthalmoplegia, supraventricular tachycardia, scoliosis, lordosis
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000178453	SCV000265719	pathogenic	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
GeneDx	RCV000147436	SCV000329505	pathogenic	not provided	2022-04-12	criteria provided, single submitter	clinical testing	Observed in homozygous state or with a pathogenic variant on the opposite allele (in trans) in patients in published literature with an RYR1-related myopathy and not observed in homozygous state in controls (McKie et al., 2014; Todd et al., 2015); Identified in a patient in published literature with a second RYR1 variant and history of congenital myopathy with episodes of generalized atypical normokalemic paralysis as a teen (Zhou et al., 2010); 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; This variant is associated with the following publications: (PMID: 33333461, 27447704, 25637381, 24951453, 24195946, 22473935, 23553787, 25525159, 26332594, 25127990, 27854218, 26633545, 29298851, 30155738, 26578207, 30609409, 30611313, 31680349, 34426522, 34539730, 25476234, 20080402)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000147436	SCV000609573	pathogenic	not provided	2017-05-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000525302	SCV000660005	pathogenic	RYR1-related disorder	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2241*) 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 (rs200563280, gnomAD 0.2%). This premature translational stop signal has been observed in individuals with autosomal recessive congenital myopathy (PMID: 20080402, 22473935, 23553787, 24195946, 24951453). ClinVar contains an entry for this variant (Variation ID: 159856). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000263175	SCV000711660	pathogenic	Central core myopathy; Neuromuscular disease	2019-05-08	criteria provided, single submitter	clinical testing	The p.Arg2241X variant in RYR1 has been reported in at least 6 individuals with myopathy in the compound heterozygous state (Illingworth 2014, Zhou 2010, Klein 2012, Todd 2018) and in several homozygous affected members of one family with foetal akinesia deformation sequence/lethal multiple pterygium syndrome (McKie 2014). This nonsense variant leads to a premature termination codon at position 2241, which is predicted to lead to a truncated or absent protein. This variant has also been reported in ClinVar (Variation ID 159856). This variant was also identified in 23/10348 of Ashkenazi Jewish and in 18/128888 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org/). However, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide further evidence that this variant causes nonsense mediated RNA decay (Zhou 2010). Loss of function in the RYR1 gene is associated with myopathies including central core disease, multi-minicore disease, centronuclear myopathy, and congenital fiber type disproportion. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive RYR1-related myopathy. ACMG/AMP Criteria applied: PVS1, PM3_Very strong, PP1_moderate.
PreventionGenetics, part of Exact Sciences	RCV000147436	SCV000852727	pathogenic	not provided	2016-06-01	criteria provided, single submitter	clinical testing
Center for Reproductive Medicine, Peking University Third Hospital	RCV001257398	SCV001433926	pathogenic	Hydrops fetalis	2019-10-16	criteria provided, single submitter	clinical testing
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	RCV001530191	SCV001739483	likely pathogenic	Central core myopathy	2020-02-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000147436	SCV002019953	pathogenic	not provided	2022-04-18	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000147436	SCV002501108	pathogenic	not provided	2021-05-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000171129	SCV002600320	pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2022-10-06	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.6721C>T (p.Arg2241X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00016 in 251116 control chromosomes (gnomAD). c.6721C>T has been reported in the literature in multiple compound heterozygous individuals affected with RYR-1 related myopathies (e.g. Zhou_2010, Klein_2012, Garibaldi_2019), in addition, the variant was also reported in homozygous state in 6 fetuses presenting as lethal fetal akinesia in one family (McKie_2014). These data indicate that the variant is very likely to be associated with disease. Publications also reported absent allele specific mRNA, and very low levels of RYR1 protein expression in muscle biopsy samples from compound heterozygous patients, providing evidence for nonsense mediated mRNA decay (e.g. Zhou_2010, Garibaldi_2019). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic (n=9) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000178453	SCV002761441	pathogenic	Malignant hyperthermia, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing	PVS1, PM2, PS4 - supporting
Fulgent Genetics, Fulgent Genetics	RCV002505131	SCV002807636	pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-09-27	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000525302	SCV004046178	pathogenic	RYR1-related disorder		criteria provided, single submitter	clinical testing	This nonsense variant found in exon 41 of 106 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous and homozygous change in patients with multi-minicore disease and fetal akinesia deformation sequence syndrome (PMID: 20080402, 34539730, 24951453, 25476234). The c.6721C>T (p.Arg2241Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.015% (43/282472) and is absent in the homozygous state, thus it is presumed to be rare. Based on the available evidence, the c.6721C>T (p.Arg2241Ter) variant is classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000178453	SCV004820892	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 41 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 not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 159856). This variant has been identified in 43/282472 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) (clinicalgenome.org). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000171129	SCV005200879	pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2024-04-08	criteria provided, single submitter	clinical testing	PVS1, PM2, PM3
CSER _CC_NCGL, University of Washington	RCV000148787	SCV000190525	likely benign	Multi-minicore disease and atypical periodic paralysis	2014-06-01	no assertion criteria provided	research
OMIM	RCV000171129	SCV000223695	pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2014-12-05	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000147436	SCV001808716	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000147436	SCV001957654	pathogenic	not provided		no assertion criteria provided	clinical testing
deCODE genetics, Amgen	RCV000178453	SCV004022261	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-07-21	no assertion criteria provided	research	The variant NM_000540.3:c.6721C>T (chr19:38496466) in RYR1 was detected in 2 heterozygotes out of 58K WGS Icelanders (MAF= 0,002%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic.