ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.488G>A (p.Arg163His)

gnomAD frequency: 0.00001  dbSNP: rs193922753
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen RCV001592963 SCV001816181 uncertain significance Malignant hyperthermia, susceptibility to, 1 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 163 of the RYR1 protein, p.(Arg163His). 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:30236257). 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 (0.864) supports a pathogenic status for this variant, PP3_Moderate. While another variant has been assessed as pathogenic at this codon, p.(Arg163Cys), PM5 is not implemented as the Grantham difference between arginine and histidine is not greater than the difference between arginine and cysteine. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. 
Fulgent Genetics, Fulgent Genetics RCV002507354 SCV002816723 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 2021-09-06 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV003992390 SCV004810768 uncertain significance not provided 2024-03-01 criteria provided, single submitter clinical testing RYR1: PM1, PP3, PS4:Supporting
All of Us Research Program, National Institutes of Health RCV001592963 SCV004828268 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-12-01 criteria provided, single submitter clinical testing

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