Submissions for variant NM_000540.3(RYR1):c.6730C>T (p.Arg2244Trp)

gnomAD frequency: 0.00004  dbSNP: rs772753793

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000320665	SCV000412370	uncertain significance	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000384512	SCV000412371	uncertain significance	Multiminicore myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000290212	SCV000412372	uncertain significance	Malignant hyperthermia of anesthesia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000345210	SCV000412373	uncertain significance	Central core myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV001295467	SCV001484387	uncertain significance	RYR1-related disorder	2022-08-01	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 2244 of the RYR1 protein (p.Arg2244Trp). This variant is present in population databases (rs772753793, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 329054). 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	RCV002487449	SCV002779080	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	2021-09-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995868	SCV004820893	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 2244 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). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 18/282504 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.