ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.6721C>T (rs200563280)

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Total submissions: 12
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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
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000147436 SCV000230536 pathogenic not provided 2015-02-19 criteria provided, single submitter clinical testing
Baylor Genetics RCV000171129 SCV000245532 pathogenic Minicore 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 2018-02-08 criteria provided, single submitter clinical testing The R2241X pathogenic variant in the RYR1 gene has been previously reported in both the homozygous and compound heterozygous state in multiple individuals with RYR1-related disorders (Zhou et al., 2010; McKie et al., 2014; Todd et al., 2015). Functional studies have demonstrated the R2241X variant results in nonsense mediated mRNA decay; as the allele carrying the nonsense variant was not amplified from mRNA (Zhou et al., 2010). The R2241X variant is observed in 22/10140 (0.217%) alleles from individuals of Ashkenazi Jewish background and 40/276908 total alleles in large population cohorts (Lek et al., 2016). Therefore, we interpret R2241X to be a pathogenic variant.
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
Invitae RCV000525302 SCV000660005 pathogenic RYR1-Related Disorders 2020-01-13 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. This variant is present in population databases (rs200563280, ExAC 0.03%). This variant has been reported in the compound heterozygous state in multiple individuals affected with autosomal recessive congenital myopathy (PMID: 24951453, 20080402, 24195946, 23553787, 22473935). ClinVar contains an entry for this variant (Variation ID: 159856, 224660). Loss-of-function variants in RYR1 are known to cause autosomal recessive RYR1-related disorders (PMID: 23919265, 20583297). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare 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 ( 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,PreventionGenetics 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
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 Minicore myopathy with external ophthalmoplegia 2014-12-05 no assertion criteria provided literature only

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