Submissions for variant NM_000540.3(RYR1):c.742G>T (p.Gly248Trp)

dbSNP: rs1801086

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002008037	SCV002264242	likely pathogenic	RYR1-related disorder	2024-06-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 248 of the RYR1 protein (p.Gly248Trp). This variant is present in population databases (rs1801086, gnomAD 0.01%). 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: 1476084). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. This variant disrupts the p.Gly248 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15448513, 18564801). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV004011032	SCV004820723	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with tryptophan at codon 248 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 3/282572 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.742G>C (p.Gly248Arg) and c.742G>A (p.Gly248Arg), are considered to be pathogenic (ClinVar variation ID: 133203, 12965), suggesting that Gly at this position is important for RYR1 protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699607	SCV005205106	uncertain significance	not specified	2024-06-06	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.742G>T (p.Gly248Trp) results in a non-conservative amino acid change located in the MIR motif domain (IPR016093) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251188 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.742G>T has been reported in the literature in a setting of whole genome sequencing in at least one individual affected with malignant hypothermia (e.g. Foo_2022). This report does not provide sufficient evidence to allow unequivocal conclusions about association of the variant with Malignant hypothermia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, different variants located at the same codon (c.742G>C or c.742G>A resulting in p.Gly248Arg) have been classified as pathogenic in ClinVar, supporting a critical relevance of this residue to RYR1 protein function. The following publication has been ascertained in the context of this evaluation (PMID: 35361824). ClinVar contains an entry for this variant (Variation ID: 1476084). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005025566	SCV005647450	likely pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; King Denborough syndrome	2024-06-07	criteria provided, single submitter	clinical testing