ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.1882C>T (p.Arg628Cys)

gnomAD frequency: 0.00001  dbSNP: rs757284447
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics, Fulgent Genetics RCV002485820 SCV002792562 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 2021-09-03 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002535003 SCV003248665 uncertain significance RYR1-related disorder 2024-06-28 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 628 of the RYR1 protein (p.Arg628Cys). This variant is present in population databases (rs757284447, gnomAD 0.02%). This missense change has been observed in individual(s) with statin myopathy (PMID: 30325262). ClinVar contains an entry for this variant (Variation ID: 590491). 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%. 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.
Revvity Omics, Revvity RCV000721432 SCV003815020 uncertain significance not provided 2023-12-07 criteria provided, single submitter clinical testing
Breakthrough Genomics, Breakthrough Genomics RCV000721432 SCV005194581 uncertain significance not provided criteria provided, single submitter not provided
PreventionGenetics, part of Exact Sciences RCV002535003 SCV000852499 uncertain significance RYR1-related disorder 2023-12-13 no assertion criteria provided clinical testing The RYR1 c.1882C>T variant is predicted to result in the amino acid substitution p.Arg628Cys. This variant was reported in an 77 year old individual with presumed statin-associated myopathy; however, additional support for pathogenicity was not provided (Case 2048 in Isackson et al 2018. PubMed ID: 30325262). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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