ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.5995C>T (p.Arg1999Cys)

dbSNP: rs767508472
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001047012 SCV001210941 pathogenic RYR1-related disorder 2024-06-17 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 1999 of the RYR1 protein (p.Arg1999Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of autosomal recessive RYR1-related conditions (PMID: 25326637; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 844219). 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%. For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health RCV004803406 SCV005425020 uncertain significance Malignant hyperthermia, susceptibility to, 1 2024-09-23 criteria provided, single submitter clinical testing

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