Submissions for variant NM_000540.3(RYR1):c.4003C>T (p.Arg1335Cys)

gnomAD frequency: 0.00003  dbSNP: rs767382534

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001297396	SCV001486408	uncertain significance	RYR1-related disorder	2022-07-15	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 1335 of the RYR1 protein (p.Arg1335Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with myopathy (PMID: 31165076). ClinVar contains an entry for this variant (Variation ID: 1001143). 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 not expected to disrupt RYR1 protein function. 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.
GeneDx	RCV001806100	SCV002050471	uncertain significance	not provided	2021-07-01	criteria provided, single submitter	clinical testing	Reported in an individual with myopathy and dysmorphic features who harbored a second variant of uncertain significance in RYR1 in unknown phase (Zullo et al., 2019); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31165076, 22473935, 20681998, 27535533)
Breda Genetics srl	RCV002291504	SCV002583841	uncertain significance	Central core myopathy	2022-05-17	criteria provided, single submitter	clinical testing	The variant c.4003C>T (p.Arg1335Cys) in the RYR1 gene is reported with uncertain significance for RYR1-related disorders in ClinVar (Variation ID: 1001143). The variant is reported with an estimated allele frequency of 0.00002955 in gnomAD exomes with no homozygous individuals reported. The nucleotide position is moderately conserved across 35 mammalian species (GERP RS: 2.78). In silico analysis gives inconsistent results.
Fulgent Genetics, Fulgent Genetics	RCV002504438	SCV002815688	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	2022-01-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004004975	SCV004821000	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1335 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 1001143; PMID: 31165076). This variant has been identified in 5/169186 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.