Submissions for variant NM_000540.3(RYR1):c.14474G>A (p.Arg4825His)

gnomAD frequency: 0.00001  dbSNP: rs193922875

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001040954	SCV001204547	pathogenic	RYR1-related disorder	2024-01-26	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 4825 of the RYR1 protein (p.Arg4825His). This variant is present in population databases (rs193922875, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia susceptibility (PMID: 36283893). ClinVar contains an entry for this variant (Variation ID: 839243). 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 95%. This variant disrupts the p.Arg4825Cys amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11709545, 17204937, 35081925, 35428369). 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.
Fulgent Genetics, Fulgent Genetics	RCV002481884	SCV002794485	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	2021-09-14	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003130110	SCV003814453	uncertain significance	not provided	2022-11-16	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004819235	SCV005440648	likely pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; King Denborough syndrome		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Strong+PS4_Supporting
PreventionGenetics, part of Exact Sciences	RCV001040954	SCV005356127	uncertain significance	RYR1-related disorder	2024-08-27	no assertion criteria provided	clinical testing	The RYR1 c.14474G>A variant is predicted to result in the amino acid substitution p.Arg4825His. This variant has been reported in an individual with myalgia and neuromuscular complications (Table A, Janssens et al. 2022. PubMed ID: 36283893). It is reported in 0.0053% of alleles in individuals of European (non-Finnish) descent in gnomAD v2; however, in gnomAD v4 (available only on GRCh38), this variant is reported in 54 of 1614036 of alleles which may be too common for an autosomal dominant variant. An alternate nucleotide change affecting the same amino acid (p.Arg4825Cys) has been reported in several individuals with core myopathies (Table 1, Zhang et al. 2022. PubMed ID: 35081925; Table 1, Fusto et al. 2022. PubMed ID: 35428369; Table 1, Herasse et al. 2007. PubMed ID: 17204937) and was shown to segregate with central core disease in a family (Monnier et al. 2001. PubMed ID: 11709545). The c.14474G>A variant has conflicting classifications in ClinVar ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/839243/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.