Submissions for variant NM_000540.3(RYR1):c.2320G>A (p.Gly774Arg)

gnomAD frequency: 0.00019  dbSNP: rs147918857

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV002051713	SCV000700138	uncertain significance	Malignant hyperthermia of anesthesia	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing for an unrelated indication. No known history of malignant hyperthermia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
PreventionGenetics, part of Exact Sciences	RCV000721448	SCV000852518	uncertain significance	not provided	2016-03-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818848	SCV000959482	uncertain significance	RYR1-related disorder	2022-10-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 774 of the RYR1 protein (p.Gly774Arg). This variant is present in population databases (rs147918857, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 496666). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
GeneDx	RCV000721448	SCV001773137	uncertain significance	not provided	2024-07-24	criteria provided, single submitter	clinical testing	Identified in a fetus with multiple congenital anomalies; however, a second RYR1 variant was not detected and information regarding parental testing was not available (PMID: 32304219); 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: 30325262, 32304219, 37937776)
Fulgent Genetics, Fulgent Genetics	RCV002506405	SCV002797725	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	2021-09-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000721448	SCV003814990	uncertain significance	not provided	2023-05-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000721448	SCV004141584	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	RYR1: PP3
Molecular Genetics, Royal Melbourne Hospital	RCV003994034	SCV004812562	uncertain significance	RYR1-related myopathy	2024-02-05	criteria provided, single submitter	clinical testing	This sequence change in RYR1 is predicted to replace glycine with arginine at codon 774, p.(Gly774Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in exon 19. There is a large physicochemical difference between glycine and arginine. The highest population minor allele frequency in gnomAD v4.0 is 0.03% (354/1,180,014 alleles) in the European (non-Finnish) population. This variant has been observed heterozygous in multiple individuals with inconsistent phenotypes or an alternative cause of disease was identified (PMID: 24627108, 27545679, 30325262, 32304219), and has been reported compound heterozygous (confirmed in trans) with a variant of uncertain significance in an individual with global developmental delay (DECIPHER). This variant has been observed in at least one individual with a negative in vitro contracture test (PMID: 32236737). Computational evidence is uninformative for the missense substitution (REVEL = 0.623). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting.
All of Us Research Program, National Institutes of Health	RCV004002451	SCV004820768	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 774 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 RYR1-related disorders in the literature. This variant has been identified in 71/282750 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003994034	SCV005399092	uncertain significance	RYR1-related myopathy	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with RYR1-related disorders (OMIM). Gain of function mechanism has been described in the context of malignant hyperthermia susceptibility (MIM#145600) and monoallelic central core disease and congenital neuromuscular disease with uniform type 1 fiber (MIM#117000). Biallelic central core disease, congenital neuromuscular disease with uniform type 1 fiber (MIM#117000) and minicore myopathy with external ophthalmoplegia (MIM#255320) are associated with a loss of function mechanism (PMIDs: 27855725, 23919265). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 71 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated SPRY domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported in an individual with rhabdomyolysis, who was malignant hyperthermia negative on an in vitro contracture test (PMID: 32236737). This variant has been reported as a VUS in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000721448	SCV002036578	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000721448	SCV002037939	uncertain significance	not provided		no assertion criteria provided	clinical testing