ClinVar Genomic variation as it relates to human health

This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of arginine with glutamine at codon 3772 of the RYR1 protein, p.(Arg3772Gln). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, a frequency consistent with pathogenicity for MHS. This variant has been reported in eight unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, seven of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, three of these individuals were homozygous for this variant and were not considered for PS4, PS4_Moderate was applied (PMID: 30236257, 17483490). This variant segregates with MHS in at least seven individuals, PP1_Strong (PMID:19645060, 22473935). This variant has been identified in an individual with a negative IVCT/CHCT result. BS2_Moderate (PMID: 30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.888) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PP1_Strong, PP3_Moderate, BS2_Moderate.

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.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 3772 of the RYR1 protein (p.Arg3772Gln). This variant is present in population databases (rs193922839, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive RYR1-related myopathy and malignant hyperthermia susceptibility (PMID: 17483490, 19645060). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133012). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg3772 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19191329, 21062345, 23919265, 24091937). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The c.11315G>A (p.R3772Q) alteration is located in exon 79 (coding exon 79) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 11315, causing the arginine (R) at amino acid position 3772 to be replaced by a glutamine (Q)._x000D_ _x000D_ Based on the available evidence, the RYR1 c.11315G>A (p.R3772Q) alteration is classified as likely pathogenic for autosomal dominant malignant hyperthermia susceptibility (MHS) and autosomal recessive RYR1-related myopathy; however, its clinical significance for autosomal dominant RYR1-related myopathy is unclear. Based on data from gnomAD, the A allele has an overall frequency of 0.002% (5/281314) total alleles studied. This variant has been reported in multiple unrelated individuals who had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT), or who have a personal or family history of a malignant hyperthermia reaction (Zhou, 2007; Carpenter, 2009; Klein, 2012; Miller, 2018). In addition, this alteration has been observed in the homozygous or compound heterozygous state in multiple individuals with myopathy (Zhou, 2007; Monnier, 2008; Carpenter, 2009; Klein, 2012; Hwang, 2012; Maggi, 2013; Stehlíková, 2017; Miller, 2018; Babi Boovi, 2021). This variant has been observed to segregate with autosomal dominant malignant hyperthermia susceptibility (MHS) and/or autosomal recessive myopathy in multiple families (Carpenter, 2009; Klein, 2012). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30236257, 23919265, 19191329, 18253926, 21911697, 21795085, 23553787, 23394784, 27447704, 27377473, 23069638, 31447099, 24091937, 21062345, 30689883, 22473935, 19645060, 17483490, 34106991)

This variant has been previously reported as a heterozygous change in patients with malignant hyperthermia (PMID: 19645060, 30236257) and as a homozygous change in patients with congenital myopathy (PMID: 17483490, 19645060, 23553787). It is present in the heterozygous state in the gnomAD population database at a frequency of .002% (5/281314) and thus is presumed to be rare. The c.11315G>A (p.Arg3772Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.11315G>A (p.Arg3772Gln) variant is classified as Pathogenic.

This variant has been reported in multiple individuals with malignant hyperthermia susceptibility (PMID: 19645060, 30236257, 17483490, 22473935, 23553787, 35849058). This variant is present in 5/281314 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant has been reported to co-segregate with disease in seven affected individuals (PMID: 19645060, 22473935). This variant is predicted to be deleterious by in silico analysis.