Submissions for variant NM_000540.3(RYR1):c.13672C>T (p.Arg4558Trp)

gnomAD frequency: 0.00001  dbSNP: rs771741606

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001449981	SCV001653530	uncertain significance	Malignant hyperthermia of anesthesia	2023-04-06	reviewed by expert panel	curation	This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of arginine with tryptophan at codon 4558 of the RYR1 protein, p.(Arg4558Trp). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID: 30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.79 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552685	SCV000659824	pathogenic	RYR1-related disorder	2024-05-22	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 4558 of the RYR1 protein (p.Arg4558Trp). This variant is present in population databases (rs771741606, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal recessive centronuclear myopathy (PMID: 28269792, 28818389, 32403337). ClinVar contains an entry for this variant (Variation ID: 478187). 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.Arg4558 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17226826, 18253926, 25747005). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
NeuroMeGen, Hospital Clinico Santiago de Compostela	RCV000754735	SCV000882623	likely pathogenic	Central core myopathy	2018-10-08	criteria provided, single submitter	clinical testing
GeneDx	RCV003238776	SCV003936337	likely pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing	Reported in association with centronuclear myopathy in patients who harbored additional variants in the RYR1 gene; however, segregation information was not provided (PMID: 32403337, 35627144); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25747005, 18253926, 17226826, 34426522, 28269792, 35627144, 33458582, 32403337, 28818389, 30236257)
PreventionGenetics, part of Exact Sciences	RCV000552685	SCV004107959	likely pathogenic	RYR1-related disorder	2023-01-09	criteria provided, single submitter	clinical testing	The RYR1 c.13672C>T variant is predicted to result in the amino acid substitution p.Arg4558Trp. This variant has been reported, along with another RYR1 variant, in individuals with centronuclear myopathy or other RYR1-related myopathies (Family E, Abath Neto et al. 2017. PubMed ID: 28818389; P5 and P6, Samoes et al. 2017. PubMed ID: 28269792; Supplementary Data, Patient ID: P47, Gonzalez-Quereda et al. 2020. PubMed ID: 32403337). Another variant impacting the same amino acid, p.Arg4558Gln, was reported in the compound heterozygous state in individuals with central core disease (Kossugue et al. 2007. PubMed ID: 17226826; Monnier et al. 2008. PubMed ID: 18253926). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-39061259-C-T) and has conflicting interpretations regarding its pathogenicity ranging from uncertain significance to likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/478187/). Of note, the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel determined this variant was of uncertain significance in regard to autosomal dominate malignant hyperthermia. Taken together, we interpret this variant as likely pathogenic for autosomal recessive disease and uncertain for autosomal dominant malignant hyperthermia.
All of Us Research Program, National Institutes of Health	RCV003999487	SCV004816241	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 4558 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 a family affected with malignant hyperthermia susceptibility (PMID: 30236257), this variant is also associated with different phenotypes (ClinVar Variation ID: 478187). This variant has been identified in 1/251486 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000754735	SCV004847257	likely pathogenic	Central core myopathy	2023-02-02	criteria provided, single submitter	clinical testing	The p.Arg4558Trp variant in RYR1 has been reported in 4 individuals with RYR1 related myopathies in the compound heterozygous state with a second RYR1 variant (2 confirmed pathogenic or likely pathogenic) (Neto 2017 PMID: 28818389, Gonzalez-Quereda 2020 PMID 32403337, Cotta 2022 PMID: 35627144). It was also identified in 0.001% (1/68028) of European chromosomes by gnomAD, v.3 (http://gnomad.broadinstitute.org), and is reported in ClinVar (Variation ID 478187). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additional variants involving this codon (p.Arg4558Gln, p.Arg4558Gly) have been identified in individuals with RYR1-related myopathies and are classified as likely pathogenic/pathogenic in ClinVar. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive RYR1-related myopathies. ACMG/AMP criteria applied: PM3_Strong, PM5, PM2_Supporting, PP3.