Submissions for variant NM_000540.3(RYR1):c.6617C>T (p.Thr2206Met) (rs118192177)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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
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.
Invitae	RCV000655558	SCV000777489	pathogenic	RYR1-Related Disorders	2019-12-20	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). 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.
PreventionGenetics,PreventionGenetics	RCV000119662	SCV000852722	pathogenic	not provided	2018-01-08	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000119662	SCV001249986	pathogenic	not provided	2017-07-01	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000606881	SCV001370553	pathogenic	Malignant hyperthermia susceptibility	2020-05-05	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.6617C>T (p.Thr2206Met) results in a non-conservative amino acid change located in the RIH domain (IPR000699) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251224 control chromosomes (gnomAD). c.6617C>T has been reported in the literature in numerous individuals affected with Malignant Hyperthermia Susceptibility and was also shown to co-segregate with disease in families (e.g. Manning_1998, Carpenter_2009, Brandom_2013, Klinger_2014). Functional studies have shown the variant to disrupt cellular calcium homeostasis (e.g. Wehner_2002). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics,Johns Hopkins University	RCV000013846	SCV001425408	pathogenic	Malignant hyperthermia, susceptibility to, 1	2020-05-21	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000013846	SCV001434860	pathogenic	Malignant hyperthermia, susceptibility to, 1	2019-06-17	criteria provided, single submitter	clinical testing	The c.6617C>T (p.Thr2206Met) variant in the RYR1 gene has been reported in multiple unrelated individuals affected with malignant hyperthermia (PMID 9497245, 12220451, 19648156) and is extremely rare in general population databases. Multiple independent in vitro experiments showed this variant is functionally damaging (PMID 12220451, 19648156, 27586648). Multiple in silico algorithms also predicted this p.Thr2206Met change to be deleterious. Therefore, this c.6617C>T (p.Thr2206Met) variant in the RYR1 gene is classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000013846	SCV001440599	pathogenic	Malignant hyperthermia, susceptibility to, 1	2019-01-01	criteria provided, single submitter	clinical testing
OMIM	RCV000013846	SCV000034093	risk factor	Malignant hyperthermia, susceptibility to, 1	2002-08-01	no assertion criteria provided	literature only
Leiden Muscular Dystrophy (RYR1)	RCV000119662	SCV000154569	not provided	not provided		no assertion provided	not provided
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