Submissions for variant NM_000540.3(RYR1):c.13673G>A (p.Arg4558Gln)

gnomAD frequency: 0.00001  dbSNP: rs118192130

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001132049	SCV001816166	uncertain significance	Malignant hyperthermia, susceptibility to, 1	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 Glutamine at codon 4558 of the RYR1 protein, p.(Arg4558Gln). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.0001, a frequency consistent with pathogenicity for MHS. This variant has been reported in individuals with a personal or family history of congenital myopathy. 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 >0.85 (0.957) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate.
Genetic Services Laboratory, University of Chicago	RCV000119483	SCV000194806	likely pathogenic	not provided	2014-03-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000119483	SCV000703968	uncertain significance	not provided	2017-01-06	criteria provided, single submitter	clinical testing
Invitae	RCV000685437	SCV000812918	pathogenic	RYR1-related disorder	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4558 of the RYR1 protein (p.Arg4558Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal recessive central core disease (PMID: 17226826, 18253926, 25747005). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65984). 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%. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000056231	SCV000915830	likely pathogenic	Central core myopathy	2019-01-10	criteria provided, single submitter	clinical testing	The RYR1 c.13673G>A (p.Arg4558Gln) variant has been reported in three studies in which it was found in a compound heterozygous state in a total of five probands with central core disease from three families (Kossugue et al. 2007; Monnier et al. 2008; Remiche et al. 2015). In two of the families, the heterozygous parent of the probands was shown to be unaffected, and in one family, the heterozygous sibling was also unaffected (Kossugue et al. 2007; Remiche et al. 2015). The p.Arg4558Gln variant was absent from 200 control chromosomes and is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project. However, this frequency is based on one allele only, suggesting the variant is rare. Western blotting revealed reduced RYR1 protein expression in the muscle tissue of one proband (Monnier et al. 2008). The amino acid residue affected by the p.Arg4558Gln variant is evolutionarily conserved and is located in the M5 transmembrane fragment of the calcium channel. Based on the collective evidence, the p.Arg4558Gln variant is classified as likely pathogenic for pathogenicity for central core disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000056231	SCV001445958	likely pathogenic	Central core myopathy	2020-11-16	criteria provided, single submitter	curation	The heterozygous p.Arg4558Gln variant in RYR1 was identified by our study in the compound heterozygous state, along with a variant of uncertain significance, in 1 individual with central core myopathy. The p.Arg4558Gln variant has been reported in at least 5 individuals of Belgian or unknown ethnicity with central core myopathy (PMID: 18253926, 25747005, 17226826) and segregated with disease in 2 affected relatives from 2 families. This variant has been identified in 0.01% (2/19952) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs118192130). The p.Arg4558Gln variant has also been reported in ClinVar (Variation ID: 65984) with conflicting interpretations of pathogenicity. In vitro functional studies provide some evidence that the variant may impact protein function (PMID: 18253926). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a reported likely pathogenic variant and in combination with a reported variant of uncertain significance that is confirmed in trans, and in 5 individuals with central core myopathy increases the likelihood that the variant is pathogenic (Variation ID: 65925, 133116; PMID: 18253926, 25747005, 17226826). Multiple variants in the same region as p.Arg4558Gln have been reported in association with disease in ClinVar, and the variant is located in a region of RYR1 that is essential to protein folding and stability, suggesting that this variant is in a hotspot and supports pathogenicity (PMID: 23069638). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2_supporting, PS3_moderate, PP3, PM3_supporting, PM1, PP1 (Richards 2015).
Baylor Genetics	RCV000056231	SCV001527384	uncertain significance	Central core myopathy	2018-03-02	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000119483	SCV002575357	likely pathogenic	not provided	2023-05-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26332594, 25637381, 17226826, 18253926, 25747005, 33458582, 35627144)
Revvity Omics, Revvity	RCV000119483	SCV003814439	uncertain significance	not provided	2022-07-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000685437	SCV004107304	likely pathogenic	RYR1-related disorder	2023-06-02	criteria provided, single submitter	clinical testing	The RYR1 c.13673G>A variant is predicted to result in the amino acid substitution p.Arg4558Gln. This variant has been reported in the compound heterozygous state in two siblings with central core disease with the heterozygous carrier parent showing no symptoms of RYR1-related disorders (Kossugue et al 2007. PubMed ID: 17226826). This variant was observed with a second RYR1 loss-of-function variant in four additional patients with congenital myopathy (Monnier N et al 2008. PubMed ID: 18253926; Remiche et al. 2015. PubMed ID: 25747005; Pinto et al. 2022. PubMed ID: 35548885). One of these patients was reported to have had surgery in the past with no adverse effects from anesthesia and carrier family members did not have symptoms (Remiche et al. 2015. PubMed ID: 25747005 ). A different substitution of this amino acid (p.Arg4558Trp) has also been reported in cases of autosomal recessive RYR1-related disorders (Gonzalez-Quereda L et al 2020. PubMed ID: 32403337; Abath Neto et al 2017. PubMed ID: 28818389). Of note, this variant has been reported in ClinVar by an ClinGen Expert Malignant Hyperthermia panel as uncertain in regard to MH susceptibility (https://www.ncbi.nlm.nih.gov/clinvar/variation/65984/). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-39061260-G-A). In summary, we categorize the c.13673G>A variant as likely pathogenic for autosomal recessive RYR1-related disorders; however, the clinical significance of this variant is uncertain in regard to autosomal dominant RYR1-related disorders.
All of Us Research Program, National Institutes of Health	RCV001132049	SCV004816242	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine 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 not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although this variant is associated with other phenotypes (ClinVar Variation ID: 65984). This variant has been identified in 10/282878 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	RCV004017359	SCV004847592	likely pathogenic	Centronuclear myopathy	2020-08-11	criteria provided, single submitter	clinical testing	The p.Arg4558Gln variant in RYR1 has been reported, in the compound heterozygous state, in 3 individuals with autosomal recessive central core myopathy and segregated with disease in 2 affected family members from 2 families (Kossugue 2007 PMID: 17226826, Monnier 2008 PMID: 18253926, Remiche 2015 PMID: 25747005).This variant has been reported in ClinVar (Variation ID 65984) and has also been identified in 2/19952 of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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 central core myopathy. ACMG/AMP Criteria applied: PM3_Strong, PP3, PM2, PP1_Moderate.
GeneReviews	RCV000056231	SCV000087320	pathologic	Central core myopathy	2010-05-11	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Leiden Muscular Dystrophy (RYR1)	RCV000119483	SCV000154390	not provided	not provided		no assertion provided	not provided
CSER _CC_NCGL, University of Washington	RCV000056231	SCV000190567	uncertain significance	Central core myopathy	2014-06-01	no assertion criteria provided	research