ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.11315G>A (p.Arg3772Gln) (rs193922839)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415300 SCV000492986 uncertain significance Scoliosis; Proximal muscle weakness; Delayed gross motor development; Pelvic girdle muscle weakness; Progressive distal muscle weakness 2014-08-29 criteria provided, single submitter clinical testing
GeneDx RCV000119432 SCV000322470 pathogenic not provided 2017-11-22 criteria provided, single submitter clinical testing The R3772Q variant in the RYR1 gene has been reported previously in the compound heterozygous and homozygous state in individuals with core congenital myopathies (Zhou et al., 2007; Monnier et al., 2008; Carpenter et al., 2009; Klein et al., 2011; Klein et al., 2012; Maggi et al., 2013; Zhou et al., 2013). Some individuals homozygous for the R3772Q variant with both myopathy and malignant hyperthermia susceptibility have been reported; in addition, some of their family members heterozygous for R3772Q had malignant hyperthermia susceptibility but no myopathy phenotype (Zhou et al., 2007; Carpenter et al., 2009; Zhou et al., 2013). The R3772Q variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R3772Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R3772Q as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000119432 SCV000596906 likely pathogenic not provided 2015-10-22 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000610269 SCV000731705 pathogenic Malignant hyperthermia susceptibility; Neuromuscular Diseases 2017-11-01 criteria provided, single submitter clinical testing The p.Arg3772Gln variant in RYR1 has been reported in the heterozygous state in 1 individual with a malignant hyperthermia susceptibility (MHS) phenotype (Carpe nter 2009) and in the homozygous or compound heterozygous state in at least 10 i ndividuals with congenital myopathy (Zhou 2007, Monnier 2008, Carpenter 2009, Kl ein 2012). Three of the individuals with congenital myopathy also have a MHS phe notype (Zhou 2007, Carpenter 2009, Klein 2012). This variant segregated with mal ignant hyperthermia in 9 affected relatives (8 heterozygotes and 1 homozygote) f rom 3 families (Carpenter 2009, Klein 2012) and with congenital myopathy in the homozygous or compound heterozygous state in 6 affected relatives from 3 familie s, 3 of whom who also had MH (Zhou 2007, Carpenter 2009, Klein 2012). mRNA expr ession studies from muscle biopsies of patients homozygous for the p.Arg3772Gln variant provide some evidence that it causes decreased mRNA expression (Zhou et al. 2013. This variant has been reported by other clinical laboratories in ClinV ar (Variation ID 133012) and has been identified in 2/11052 European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; d bSNP rs193922839). In summary, the p.Arg3772Gln variant meets criteria to be cla ssified as pathogenic for malignant hyperthermia in an autosomal dominant manner and congenital myopathy in an autosomal recessive manner based upon presence in multiple affected individuals, segregation studies, very low frequency in the g eneral population and functional studies.
Leiden Muscular Dystrophy (RYR1) RCV000119432 SCV000154339 not provided not provided no assertion provided not provided
PreventionGenetics RCV000119432 SCV000852244 uncertain significance not provided 2013-11-22 criteria provided, single submitter clinical testing

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