Submissions for variant NM_000540.3(RYR1):c.7355G>A (p.Arg2452Gln)

dbSNP: rs193922815

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001802872	SCV002047613	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2021-12-21	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 2452 of the RYR1 protein, p.(Arg2452Gln). 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 without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4 was not implemented (PMID: PMID:16732084). 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 >0.85 (0.928) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP3_Moderate.
CeGaT Center for Human Genetics Tuebingen	RCV000119707	SCV001249990	pathogenic	not provided	2019-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001204776	SCV001375997	likely pathogenic	RYR1-related disorder	2023-08-29	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with malignant hyperthermia (PMID: 16917943). 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. This variant disrupts the p.Arg2452 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10823104, 22030266, 22473935, 23394784, 24433488, 25086907). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 133201). This variant is present in population databases (rs193922815, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2452 of the RYR1 protein (p.Arg2452Gln).
Fulgent Genetics, Fulgent Genetics	RCV002483211	SCV002785215	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	2021-08-09	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002514607	SCV003761248	uncertain significance	RYR1-related myopathy	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Arg2542Gln variant in RYR1 was identified by our study in one individual with congenital myopathy. The p.Arg2542Gln variant in RYR1 has been previously reported in one individual with RYR1-related disease (PMID: 16917943) but has been identified in 0.001% (1/113550) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs193922815). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID:133201) and has been interpreted as pathogenic by CeGaT Center for Human Genetics Tuebingen and as a variant of uncertain significance by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel and Invitae. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region as the p.Arg2542Gln variant have been reported in association with disease in the literature, suggesting that this variant is in a hot spot and slightly supports pathogenicity (PMID: 21118704). One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg2452Trp, has been reported in association with disease in ClinVar, slightly supporting that a change at this position may not be tolerated (ClinVar Variation ID: 65979). In summary, the clinical significance of the p.Arg2542Gln variant is uncertain. ACMG/AMP Criteria applied: PM1_Supporting, PM5_Supporting, PP3 (Richards 2015).
All of Us Research Program, National Institutes of Health	RCV001802872	SCV004822582	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 2452 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 with a positive Ca2+ induced Ca2+ release test and with a family history of malignant hyperthermia susceptibility (PMID: 16732084). This variant has been identified in 1/251192 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg2452Trp is known to cause malignant hyperthermia susceptibility (ClinVar variation ID: 65979). Although there is a suspicion for a pathogenic role, the available clinical evidence for this p.Arg2452Trp variant is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
Leiden Muscular Dystrophy (RYR1)	RCV000119707	SCV000154614	not provided	not provided		no assertion provided	not provided