ClinVar

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg4825 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID: 16917943), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 65985). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia and/or central core disease and clinical features of autosomal recessive RYR1-related conditions (PMID: 11709545, 17204937, 35081925, 35428369). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 4825 of the RYR1 protein (p.Arg4825Cys).