Submissions for variant NM_000540.3(RYR1):c.3224G>A (p.Arg1075Gln)

gnomAD frequency: 0.00001  dbSNP: rs749040743

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV002051859	SCV002318985	likely benign	Malignant hyperthermia of anesthesia	2022-03-14	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 1075 of the RYR1 protein, p.(Arg1075Gln). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.000029, 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). One relative was shown to be heterozygous for the variant and IVCT negative, BS2_Moderate was implemented (PMID: 19454545). 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 0.846 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: PS4_Supporting, BS2_Moderate.
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000498485	SCV000590875	likely pathogenic	Arthrogryposis multiplex congenita	2017-05-16	criteria provided, single submitter	clinical testing	This RYR2 variant was found in compound heterozygosity with one another RYR2 variant in a fetus with polymalformative syndrome and arthrogryposis
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865575	SCV002140388	pathogenic	RYR1-related disorder	2023-12-11	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 1075 of the RYR1 protein (p.Arg1075Gln). This variant is present in population databases (rs749040743, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive centronuclear myopathy (PMID: 28818389). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 433176). 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.Arg1075 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23826317; Invitae). 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.
All of Us Research Program, National Institutes of Health	RCV004003509	SCV004820802	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1075 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, in two affected individuals and one unaffected individual (PMID: 19454545, 30236257). This variant has also been associated with other phenotypes (ClinVar Variation ID: 433176, PMID: 28818389). This variant has been identified in 1/251480 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.
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004586749	SCV005038473	likely pathogenic	Centronuclear myopathy	2024-03-01	criteria provided, single submitter	research	PM2+PM5+PP1+PP2+PP3
GeneDx	RCV004822078	SCV005442942	likely pathogenic	not provided	2024-06-25	criteria provided, single submitter	clinical testing	Reported in at least one family in which the variant was seen in two individuals with malignant hyperthermia susceptibility and in one unaffected individual, but detailed clinical and segregation information were not provided (PMID: 30236257, 19454545); 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: 28818389, 23826317, 34515413, 19454545, 30236257)