Submissions for variant NM_000540.3(RYR1):c.13990T>C (p.Cys4664Arg)

gnomAD frequency: 0.00002  dbSNP: rs759500310

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001449996	SCV001653546	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 cysteine with arginine at codon 4664 of the RYR1 protein, p.(Cys4664Arg). 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 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: 19191333). One functional study was published for this variant. In this study, immortalized B-lymphocytes from patients carrying p.(Arg530His), p.(Asn2342Ser), p.(Glu2371Gly), and p.(Arg2454His) showed increased acidification rate when stimulated by 4CmC. B-lymphocytes from patients carrying p.(Cys4664Arg) were less activated by 4CmC, indicating a leaky channel. This assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID: 19191333). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.936) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1_Supporting, PP3_Moderate.
GeneDx	RCV002259395	SCV002538727	likely pathogenic	not provided	2023-07-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: cell lines expressing C4664R showed reduced activity (Zullo et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27646467, 19191333, 20681998, 33767344)
Fulgent Genetics, Fulgent Genetics	RCV002501577	SCV002785482	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	2021-08-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002560330	SCV003443250	likely pathogenic	RYR1-related disorder	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 4664 of the RYR1 protein (p.Cys4664Arg). This variant is present in population databases (rs759500310, gnomAD 0.0009%). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility (PMID: 19191333). ClinVar contains an entry for this variant (Variation ID: 1120228). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RYR1 function (PMID: 19191333). 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.