Submissions for variant NM_000540.3(RYR1):c.14581C>T (p.Arg4861Cys)

dbSNP: rs118192181

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001802228	SCV002047657	uncertain significance	Malignant hyperthermia of anesthesia	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 cysteine at codon 4861 of the RYR1 protein, p.(Arg4861Cys). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. 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). This variant has also been reported in many individuals with myopathy without reported MH events, these individuals were not considered for PS4 as this assessment is specific to MH inherited in an autosomal dominant pattern (PMID:12565913, PMID:16621918, PMID:17226826 and others). Another variant has been assessed as likely pathogenic occurs at this codon, p.(Arg4861His), PM5_Supporting (PMID: 23558838). 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_Supporting (PMID: 21118704). A REVEL score >0.85 (0.912) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: PS4_Supporting, PM1_Supporting, PM5_Supporting, PP3_Moderate.
GeneDx	RCV000119532	SCV000329691	pathogenic	not provided	2021-11-09	criteria provided, single submitter	clinical testing	Reported in multiple individuals with autosomal dominant central core disease with histological confirmation of central cores on muscle biopsy (Davis et al., 2003; Bharucja-Goebel et al, 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12565913, 23553484, 20301565, 26684984, 32403337, 33333461, 33184643, 33458582, 20681998)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000119532	SCV000510708	pathogenic	not provided	2016-10-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000695782	SCV000824302	pathogenic	RYR1-related disorder	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 4861 of the RYR1 protein (p.Arg4861Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neonatal onset myopathy as well as central core disease (CCD) (PMID: 12565913, 17483490, 23553484, 25960145, 26684984). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 65986). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg4861 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11709545, 12565913, 16621918, 23394784, 25521991). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000119532	SCV000852432	pathogenic	not provided	2016-09-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000056233	SCV001524890	pathogenic	Central core myopathy	2019-06-21	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798767	SCV001984027	pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2024-10-04	criteria provided, single submitter	research	PS2_VeryStrong, PP4, PM2, PM5, PM1
Revvity Omics, Revvity	RCV000119532	SCV003827271	pathogenic	not provided	2023-06-26	criteria provided, single submitter	clinical testing
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV003156069	SCV003845265	pathogenic	See cases	2022-12-21	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000056233	SCV004048161	pathogenic	Central core myopathy		criteria provided, single submitter	clinical testing	The missense variant p.R4861C in RYR1 (NM_000540.3) has been reported previosuly in multiple individuals with autosomal dominant Central core disease with histological confirmation of central cores on muscle biopsy (Davis et al., 2003; Bharucha-Goebel et al, 2013 ). The p.R4861C variant is novel (not in any individuals) in gnomAD Exomes. There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.R4861C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 4861 of RYR1 is conserved in all mammalian species. The nucleotide c.14581 in RYR1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000056233	SCV005381832	likely pathogenic	Central core myopathy		criteria provided, single submitter	clinical testing	In silico analysis tools (CADD_phred, GERP, MutationTaster, REVEL) predict this variant to impair RYR1 protein function. Previously, two missense variants c.14581C>A and c.14581C>G at the same codon Arg4861Ser and Arg4861Gly has been reported in ClinVar database in patients with RYR1-related disorder (ClinVar ID: 2027376 and ClinVar ID: 943431). The variant c.14581C>T has been reported as pathogenic (13)/variant of uncertain significance (1) by 14 submitters to the ClinVar database in individuals with Central core myopathy, RYR1-related disorder and malignant hyperthermia (ClinVar ID: 65986; Davis et al., 2003). The clinical features observed in her are in concordance with congenital myopathy 1A. Thus, the above-mentioned variant in heterozygous state is interpreted to be the cause for the condition observed in the proband and her brother.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000056233	SCV005398040	pathogenic	Central core myopathy	2024-09-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with RYR1-related disorders (OMIM). Gain of function mechanism has been described in the context of malignant hyperthermia susceptibility 1 (MIM#145600) and autosomal dominant congenital myopathy 1A with susceptibility to malignant hyperthermia (MIM#117000). Autosomal recessive congenital myopathy 1B (MIM#255320) is associated with a loss of function mechanism (PMIDs: 27855725, 23919265). The mechanism of King-Denborough syndrome (MIM#619542) is unclear. (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is within one of the three enriched hotspot regions enriched for autosomal dominant RYR1 variants (PMID: 33767344). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in more than ten individuals, including at least four de novo, with RYR1-related features, particularly central core disease (ClinVar, PMID: 12565913). However, this variant has been classified as VUS for malignant hyperthermia susceptibility (MHS) by an expert panel in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000119532	SCV005875924	pathogenic	not provided	2024-09-19	criteria provided, single submitter	clinical testing	The RYR1 c.14581C>T; p.Arg4861Cys variant (rs118192181, ClinVar Variation ID: 65986) is reported in the literature in multiple individuals affected with RYR1-related myopathies, including several de novo occurrences (Bharucha-Goebel 2013, Chang 2022, Davis 2003, Lazier 2016, Wu 2006). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.916). Additionally, another variant at this codon (c.14582G>A; p.Arg4861His) has been reported in multiple individuals with RYR1-related myopathies and is considered disease-causing (Chang 2022, Davis 2003, Wu 2006). Based on available information, the p.Arg4861Cys variant is considered to be pathogenic. References: Bharucha-Goebel DX et al. Severe congenital RYR1-associated myopathy: the expanding clinicopathologic and genetic spectrum. Neurology. 2013 Apr 23;80(17):1584-9. PMID: 23553484. Chang X et al. Correlation of Phenotype-Genotype and Protein Structure in RYR1-Related Myopathy. Front Neurol. 2022 May 26;13:870285. PMID: 35693006. Davis MR et al. Principal mutation hotspot for central core disease and related myopathies in the C-terminal transmembrane region of the RYR1 gene. Neuromuscul Disord. 2003 Feb;13(2):151-7. PMID: 12565913. Lazier J et al. Bilateral congenital lumbar hernias in a patient with central core disease--A case report. Neuromuscul Disord. 2016 Jan;26(1):56-9. PMID: 26684984. Wu S et al. Central core disease is due to RYR1 mutations in more than 90% of patients. Brain. 2006 Jun;129(Pt 6):1470-80. PMID: 16621918.
3billion	RCV000056233	SCV005904049	likely pathogenic	Central core myopathy	2023-11-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.92 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.98 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000065986 /PMID: 12565913). Different missense changes at the same codon (p.Arg4861Gly, p.Arg4861His, p.Arg4861Pro, p.Arg4861Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012982, VCV000943431, VCV001066439, VCV002027376 /PMID: 11709545 /3billion dataset). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
GeneReviews	RCV000056233	SCV000087322	pathologic	Central core myopathy	2010-05-11	no assertion criteria provided	curation	Converted during submission to Pathogenic.
RYR1 database	RCV000119532	SCV000154439	not provided	not provided		no assertion provided	not provided
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000119532	SCV001928785	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000119532	SCV001958401	pathogenic	not provided		no assertion criteria provided	clinical testing