Submissions for variant NM_000540.3(RYR1):c.4816C>T (p.Arg1606Cys)

gnomAD frequency: 0.00001  dbSNP: rs774316371

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196867	SCV001367500	uncertain significance	Congenital myopathy with fiber type disproportion	2020-01-21	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP3.
GeneDx	RCV001751360	SCV001986238	uncertain significance	not provided	2019-07-02	criteria provided, single submitter	clinical testing	Reported as a paternally inherited variant in a patient with RYR1-related congenital myopathy with central nuclei; no other clinical information on patient or parents provided (Wilmshurst et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20839240)
Centogene AG - the Rare Disease Company	RCV001809991	SCV002059226	uncertain significance	Central core myopathy	2018-04-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001876279	SCV002180364	uncertain significance	RYR1-related disorder	2022-06-28	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 1606 of the RYR1 protein (p.Arg1606Cys). This variant is present in population databases (rs774316371, gnomAD 0.004%). This missense change has been observed in individual(s) with centronuclear myopathy (PMID: 20839240). ClinVar contains an entry for this variant (Variation ID: 930890). 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 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	RCV002484069	SCV002779777	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
All of Us Research Program, National Institutes of Health	RCV004010611	SCV004820846	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1606 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 autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 930890). This variant has been identified in 4/183582 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.