Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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, |
RCV000119662 | SCV000596916 | pathogenic | not provided | 2015-11-23 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular 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. |
Prevention |
RCV000119662 | SCV000852722 | pathogenic | not provided | 2018-01-08 | criteria provided, single submitter | clinical testing | |
Ce |
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, |
RCV000013846 | SCV001425408 | pathogenic | Malignant hyperthermia, susceptibility to, 1 | 2020-05-21 | criteria provided, single submitter | clinical testing | |
Human Genome Sequencing Center Clinical Lab, |
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, |
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 |
RCV000119662 | SCV000154569 | not provided | not provided | no assertion provided | not provided | ||
Developmental Genetics Unit, |
RCV000162149 | SCV000196435 | likely pathogenic | Ptosis; Sacral agenesis; History of neonatal hypotonia | 2014-12-01 | no assertion criteria provided | research |