Submissions for variant NM_000540.3(RYR1):c.4747C>T (p.Arg1583Cys)

gnomAD frequency: 0.00008  dbSNP: rs754476250

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000305865	SCV001815844	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 cysteine at codon 1583 of the RYR1 protein, p.(Arg1583Cys). The maximum allele frequency (MAF) for this variant among the six major gnomAD populations is NFE: 0.000122, a frequency consistent with pathogenicity for MHS. However, the MAF in the Finnish population is 0.0014 which is higher than expected for a single pathogenic variant. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction 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); both of these individuals had a other RYR1 variants identified in cis (p.Gly248Arg and p.Glu5034Val, likely pathogenic and VUS, PMID:19346234; p.Val2102Leu, VUS, PMID:23035052). A third individual was identified with this variant and masseter muscle rigidity (PMID:30864471), a precursor to MH. The available case data combined with the high MAF in the NFE and FIN populations in gnomAD does not allow for the use of PS4. This variant segregates with MHS in two families, however, PP1 was not implemented due to the presence of other RYR1 variants in cis (PMID:19346234, PMID:23035052). Functional studies were carried out in B-lymphoblastoid cells from three family members with both the p.Arg1583Cys and p.Val2102Leu RYR1 variants (PMID:23035052). These cells were hypersensitive to agonist compared to wild type cells, however PS3 was not implemented as all cells were from the same family (two or more independent studies are required) and other variants in cis complicated the interpretation. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.586 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented.
Illumina Laboratory Services, Illumina	RCV000359436	SCV000412193	likely benign	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000400904	SCV000412194	likely benign	Multiminicore myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000305865	SCV000412195	likely benign	Malignant hyperthermia of anesthesia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000360443	SCV000412196	likely benign	Central core myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000540830	SCV000659943	uncertain significance	RYR1-related disorder	2022-02-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1583 of the RYR1 protein (p.Arg1583Cys). This variant is present in population databases (rs754476250, gnomAD 0.2%). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions (PMID: 19346234, 23035052). ClinVar contains an entry for this variant (Variation ID: 329032). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
PreventionGenetics, part of Exact Sciences	RCV000721552	SCV000852640	uncertain significance	not provided	2015-08-18	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000721552	SCV001475425	uncertain significance	not provided	2019-12-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002487448	SCV002784006	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	2021-08-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000721552	SCV003813105	uncertain significance	not provided	2019-07-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488549	SCV004241711	uncertain significance	not specified	2023-12-27	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.4747C>T (p.Arg1583Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 166432 control chromosomes (gnomAD). The observed variant frequency is approximately 2.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility phenotype (8.8e-05), strongly suggesting that the variant is benign. c.4747C>T has been reported in the literature in individuals affected with Malignant Hyperthermia Susceptibility or Hypotonia without strong evidence of causality (e.g. Broman_2009, Schiemann_2013, Hudig_2019, Ek_2023). These reports do not provide unequivocal conclusions about association of the variant with Malignant Hyperthermia Susceptibility. Co-occurrence with another pathogenic variant was reported in affected individuals in one of these families (RYR1, p.Gly248Arg, Broman_2009), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19346234, 23035052, 30864471, 37510298, 37273706). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Six submitters classified it as uncertain significance, including a ClinGen expert panel, and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.