Submissions for variant NM_000540.3(RYR1):c.529C>T (p.Arg177Cys)

gnomAD frequency: 0.00001  dbSNP: rs193922757

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001588953	SCV001816206	pathogenic	Malignant hyperthermia, susceptibility to, 1	2021-03-16	reviewed by expert panel	curation	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 cysteine at codon 177 of the RYR1 protein, p.(Arg177Cys). This variant was not present in the six major gnomAD populations at the time this variant was interpreted. This variant has been reported in 11 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 11 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), PS4 (PMID:30236257, PMID:16163667). This variant has been identified an individual with a negative IVCT/CHCT result BS2_Moderate. In one individuals the variant was determined to be de novo with confirmed parentage PS2_Moderate. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in at least 7 individuals PP1_Strong (PMID:19648156). A REVEL score >0.85 (0.931) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS2_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534082	SCV000659960	pathogenic	RYR1-related disorder	2021-04-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. While experimental studies have shown that this missense change does not perturb the global structural integrity of RYR1 N-terminal region, the mechanism of pathogenicity for this variant is not well understood and further functional studies are needed (PMID: 19541610). This missense change is located in the N-terminal region of the RYR1 protein where a significant number of RYR1 missense mutations previously reported to cause malignant hyperthermia are found (PMID: 16084090). These observations suggest that missense substitutions within this region may affect protein function. This variant has been reported in multiple individuals affected with malignant hyperthermia (PMID: 16163667, 16835904, 21965348, 19648156, 25658027, 28078069). ClinVar contains an entry for this variant (Variation ID: 133147). This variant is present in population databases at a very low frequency (rs193922757, ExAC 0.02%). This sequence change replaces arginine with cysteine at codon 177 of the RYR1 protein (p.Arg177Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine.
GeneDx	RCV000119636	SCV001986232	uncertain significance	not provided	2019-11-12	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19541610, 19648156, 16163667, 30236257)
CeGaT Center for Human Genetics Tuebingen	RCV000119636	SCV002543914	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	RYR1: PP1:Strong, PM1, PM2, PS2:Moderate, PP3
Leiden Muscular Dystrophy (RYR1)	RCV000119636	SCV000154543	not provided	not provided		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV000534082	SCV000852679	pathogenic	RYR1-related disorder	2024-09-13	no assertion criteria provided	clinical testing	The RYR1 c.529C>T variant is predicted to result in the amino acid substitution p.Arg177Cys. This variant has been reported to be responsible for Malignant Hyperthermia (MH) in several families, including occurring de novo in one individual (Monnier et al. 2005. PubMed ID: 16163667; Robinson et al. 2006. PubMed ID: 16917943; Carpenter et al. 2009. PubMed ID: 19648156). Exon 6 is a hotspot for MH pathogenic variants in RYR1; several substitutions at nearby amino acids have been reported to be pathogenic for MH (www.emhg.org). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic.