Submissions for variant NM_000540.3(RYR1):c.14203C>T (p.Arg4735Trp)

gnomAD frequency: 0.00006  dbSNP: rs766887342

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000180769	SCV000233257	uncertain significance	not provided	2016-12-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622827	SCV000741435	uncertain significance	Inborn genetic diseases	2016-04-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810031	SCV000950217	uncertain significance	RYR1-related disorder	2024-01-24	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 4735 of the RYR1 protein (p.Arg4735Trp). This variant is present in population databases (rs766887342, gnomAD 0.02%). 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: 199248). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg4735 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID: 24433488), 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193858	SCV001363008	uncertain significance	not specified	2019-01-23	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.14203C>T (p.Arg4735Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 277056 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility (4e-05 vs 8.8e-05), allowing no conclusion about variant significance. c.14203C>T has been reported in the literature in homozygous form, in case report, describing a newborn who had severe hypotonia, similar to some other patients with mutations at different loci in RYR1, however the patient also had cerebral atrophy and dysfunction, which is unusual for RYR1-related disorders (Gilfert 2016). This report therefore does not provide unequivocal conclusions about association of the variant with Malignant Hyperthermia Susceptibility (MHS). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a study for a different missense change affecting the same amino acid (Arg4735Gln), showed pathological contractures after caffeine and halothane application, where the in vitro contracture tests were performed on a muscle biopsy specimen taken from a heterozygote patient with a history of clinical MH and a histology positive for central cores (Klingler 2014). In addition, some neighboring missense changes (p.Y4733D, p.G4734E, p.R4737Q, p.R4737W), have been reported in patients with malignant hyperthermia (HGMD). These data support the functional significance of this region. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002492795	SCV002775586	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	2021-09-07	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000180769	SCV002817216	uncertain significance	not provided	2020-09-17	criteria provided, single submitter	clinical testing	This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Revvity Omics, Revvity	RCV000180769	SCV003814384	uncertain significance	not provided	2019-11-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996590	SCV004816261	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 4735 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 the C-terminal region of the RYR1 protein (a.a. 4,631-4,991) that is considered to be a hotspot for pathogenic variants that may contribute to malignant hyperthermia susceptibility as well as other phenotype(s) (PMID: 21118704). 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: 199248). This variant has been identified in 11/282720 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.