Submissions for variant NM_000540.3(RYR1):c.1475G>A (p.Arg492His)

gnomAD frequency: 0.00007  dbSNP: rs901087791

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001580397	SCV001810082	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 histidine at codon 492 of the RYR1 protein, p.(Arg492His). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.00008, 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), (PMID:30236257). However, the high MAF in the AFR population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.81 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001358912	SCV001554769	uncertain significance	RYR1-related disorder	2022-09-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 492 of the RYR1 protein (p.Arg492His). This variant is present in population databases (no rsID available, gnomAD 0.008%). This missense change has been observed in individual(s) with malignant hyperthermia (PMID: 25658027). ClinVar contains an entry for this variant (Variation ID: 1050940). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002504585	SCV002814432	uncertain significance	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-08-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298562	SCV003997488	uncertain significance	Inborn genetic diseases	2023-03-27	criteria provided, single submitter	clinical testing	The c.1475G>A (p.R492H) alteration is located in exon 14 (coding exon 14) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 1475, causing the arginine (R) at amino acid position 492 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (4/282860) total alleles studied. The highest observed frequency was 0.008% (2/24950) of African alleles. This variant has been reported in one individual found to be malignant hyperthermia susceptible by in vitro contracture test (Fiszer, 2015). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004005259	SCV004820747	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 492 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: 25658027, 30236257) and an individual with a history of exertional heat illness diagnosed as malignant hyperthermia equivocal by in vitro contracture test (PMID: 32054689). This variant has been identified in 4/282860 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.