Submissions for variant NM_000540.3(RYR1):c.488G>A (p.Arg163His)

gnomAD frequency: 0.00001  dbSNP: rs193922753

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001592963	SCV001816181	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-04-06	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 histidine at codon 163 of the RYR1 protein, p.(Arg163His). This variant has been reported in an individual with a personal or family history of an MH episode and 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_Supporting (PMID:30236257). 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). A REVEL score >0.85 (0.864) supports a pathogenic status for this variant, PP3_Moderate. While another variant has been assessed as pathogenic at this codon, p.(Arg163Cys), PM5 is not implemented as the Grantham difference between arginine and histidine is not greater than the difference between arginine and cysteine. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. 
Fulgent Genetics, Fulgent Genetics	RCV002507354	SCV002816723	uncertain significance	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-09-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003992390	SCV004810768	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing	RYR1: PM1, PP3, PS4:Supporting
All of Us Research Program, National Institutes of Health	RCV001592963	SCV004828268	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV005092348	SCV005744296	uncertain significance	RYR1-related disorder	2024-02-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 163 of the RYR1 protein (p.Arg163His). This variant is present in population databases (rs193922753, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 635269). 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 80%. This variant disrupts the p.Arg163Cys amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8220423, 8592342, 9334205, 11524458, 19648156, 21156754). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.