Submissions for variant NM_000540.3(RYR1):c.11132C>G (p.Thr3711Arg)

dbSNP: rs375915752

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000721218	SCV000852233	uncertain significance	not provided	2017-10-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999811	SCV004828269	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with arginine at codon 3711 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 been reported in an individual affected with malignant hyperthermia susceptibility and a family affected with malignant hyperthermia susceptibility with a history of malignant hyperthermia episodes (PMID: 23558838, 28063098, 30916033, 31559918). One of the individuals affected with a malignant hyperthermia episode also carried a known pathogenic variant in the RYR1 gene that could explain the observed phenotype (PMID: 23558838, 28063098, 31559918). This variant has been identified in 1/248650 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005092111	SCV005772340	likely pathogenic	RYR1-related disorder	2024-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 3711 of the RYR1 protein (p.Thr3711Arg). This variant is present in population databases (rs375915752, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia and/or myopathy (PMID: 23558838, 32236737). ClinVar contains an entry for this variant (Variation ID: 590375). Invitae Evidence 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 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.Thr3711 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30236257, 32054689). 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.