Submissions for variant NM_000540.3(RYR1):c.2365C>T (p.Arg789Trp)

gnomAD frequency: 0.00003  dbSNP: rs765445445

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000721449	SCV000572976	uncertain significance	not provided	2017-02-02	criteria provided, single submitter	clinical testing	The R789W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R789W variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and a different missense variant (R789L) at the same position has been previously reported in an individual with myopathy who harbored an additional variant on the opposite RYR1 allele (Klein et al., 2012). In silico analysis predicts the R789W variant is probably damaging to the protein structure/function.
PreventionGenetics, part of Exact Sciences	RCV000721449	SCV000852519	uncertain significance	not provided	2015-06-24	criteria provided, single submitter	clinical testing
Invitae	RCV001216298	SCV001388088	uncertain significance	RYR1-related disorder	2022-07-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 789 of the RYR1 protein (p.Arg789Trp). This variant is present in population databases (rs765445445, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 423297). 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. This variant disrupts the p.Arg789 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID: 22473935), which suggests that this may be a clinically significant amino acid residue. 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.
Fulgent Genetics, Fulgent Genetics	RCV002475944	SCV002792515	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	2021-09-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000721449	SCV003814421	uncertain significance	not provided	2022-01-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003397	SCV004820770	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 789 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 RYR1-related disorders in the literature. This variant has been identified in 2/282864 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.