ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.6617C>T (p.Thr2206Met) (rs118192177)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Developmental Genetics Unit,King Faisal Specialist Hospital & Research Centre RCV000162149 SCV000196435 likely pathogenic Ptosis; Sacral agenesis; History of neonatal hypotonia 2014-12-01 no assertion criteria provided research
GeneDx RCV000119662 SCV000581797 pathogenic not provided 2017-11-17 criteria provided, single submitter clinical testing The T2206M pathogenic variant in the RYR1 gene has been reported previously in the heterozygous state in individuals with malignant hyperthermia and in the homozygous state in an individual with early onset muscle weakness, contractures, and elevated CPK levels (Manning et al., 1998; Monnier et al., 2005; Amburgey et al., 2013). The T2206M variant is observed in 4/126660 (0.003%) alleles from individuals of non-Finnish European background, in large population cohorts (Lek et al., 2016). The T2206M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and within the critical hotspot domain for E-C coupling (Perez et al., 2003). Functional studies have shown that T2206M affects the function of the RYR1 protein (Wehner et al., 2002; Monnier et al., 2005). We interpret T2206M as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000119662 SCV000596916 pathogenic not provided 2015-11-23 criteria provided, single submitter clinical testing
Invitae RCV000655558 SCV000777489 pathogenic RYR1-Related Disorders 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 2206 of the RYR1 protein (p.Thr2206Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs118192177, ExAC 0.006%). This variant has been reported to segregate with malignant hyperthermia in several individuals from multiple families (PMID: 9497245, 12220451, 19919814), and has been reported in numerous unrelated individuals affected with malignant hyperthermia (PMID: 16835904, 19648156, 23558838, 24433488). Additionally, this variant has been reported in individuals affected with RYR1-related myopathy, including an individual who was homozygous for this variant  (PMID: 23919265, 25558065, 25960145). ClinVar contains an entry for this variant (Variation ID: 12977). This missense change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). These observations suggest that a previously unreported missense substitution within this region may affect protein function. Experimental studies have shown that this missense change perturbs cellular calcium homeostasis (PMID: 12220451, 27586648). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000606881 SCV000712440 pathogenic Malignant hyperthermia susceptibility 2016-09-21 criteria provided, single submitter clinical testing The p.Thr2206Met variant in RYR1 has been reported in the heterozygous state in >30 individuals with malignant hyperthermia (MH) and segregated with disease in 6 relatives from 3 families (Manning 1998, Rueffert 2002, Carpenter 2009, Sambuu ghin 2001, Wehner 2002, Alazami 2015). It was also reported in the heterozygous state in at least 1 individual with multi-minicore myopathy and in the homozygou s state in 1 individual with muscular dystrophy (Amburgey 2013). Additionally, i t has been reported by other clinical laboratories in clinvar (Variation ID 1297 7) and has been identified in 5/129110 of European chromosomes by gnomAD (http:/ /gnomad.broadinstitute.org). In vitro functional studies provide some evidence t hat the p.Thr2206Met variant may impact RYR1 protein function (Wehner 2002) and computational prediction tools and conservation analysis suggest that this varia nt may impact the protein. In summary, this variant meets criteria to be classi fied as pathogenic for MH in an autosomal dominant manner based on multiple obse rvations in affected individuals, segregation studies, very low frequency in the general population and functional and computational evidence. ACMG/AMP Criteria applied: PS3_Supporting, PS4, PP1_Moderate, PP3, PM2.
Leiden Muscular Dystrophy (RYR1) RCV000119662 SCV000154569 not provided not provided no assertion provided not provided
OMIM RCV000013846 SCV000034093 risk factor Malignant hyperthermia, susceptibility to, 1 2002-08-01 no assertion criteria provided literature only
PreventionGenetics RCV000119662 SCV000852722 pathogenic not provided 2018-01-08 criteria provided, single submitter clinical testing

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