Submissions for variant NM_000540.3(RYR1):c.2044C>T (p.Arg682Trp)

dbSNP: rs776252106

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004922	SCV001164432	uncertain significance	Central core myopathy	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Arg682Trp variant in RYR1 was identified by our study in the compound heterozygous state, with a VUS, in one individual with central core disease of muscle. This variant has been identified in 0.001221% (3/245672) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs776252106). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The RYR1 gene has a low rate of benign missense variants, raising the possibility that a change in this gene may not be tolerated. In summary, the clinical significance of the p.Arg682Trp variant is uncertain. ACMG/AMP Criteria applied: PM2, PP2, PP3 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001862742	SCV002177674	likely pathogenic	RYR1-related disorder	2023-07-17	criteria provided, single submitter	clinical testing	This variant disrupts the p.Arg682 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31127727, 34411415, 35081925). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 682 of the RYR1 protein (p.Arg682Trp). This variant is present in population databases (rs776252106, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive RYR1-related conditions (PMID: 30611313). ClinVar contains an entry for this variant (Variation ID: 813941). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV002305557	SCV002599736	uncertain significance	not provided	2022-11-07	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30611313)
Fulgent Genetics, Fulgent Genetics	RCV002479200	SCV002782979	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	2021-11-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004004475	SCV004838179	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 682 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia susceptibility in the literature but has been observed in an individual with core-rod myopathy (PMID: 30611313). This variant has been identified in 3/250824 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance for malignant hyperthermia susceptibility.
PreventionGenetics, part of Exact Sciences	RCV001862742	SCV004121126	uncertain significance	RYR1-related disorder	2024-01-22	no assertion criteria provided	clinical testing	The RYR1 c.2044C>T variant is predicted to result in the amino acid substitution p.Arg682Trp. This variant was reported with a second RYR1 variant in two individuals with RYR1-related myopathy (Garibaldi et al 2019. PubMed ID: 30611313; Table S2, Cloney et al. 2022. PubMed ID: 34740920). Other substitutions of this amino acid (p.Arg682Gly, p.Arg682Gln) have also been reported with a second RYR1 in other cases of RYR1-related myopathy (Mellis et al 2022. PubMed ID: 34411415; Zhang et al 2022. PubMed ID: 35081925). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be pathogenic for autosomal recessive RYR1-related disorders, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.