ClinVar

Description

The R614C missense variant in the RYR1 gene has been reported previously in multiple individuals with malignant hyperthermia susceptibility (MHS) (Carpenter et al., 2009; Gillard et al., 1991; Gonsalves et al., 2013; Otsu et al., 1994; Vladutiu et al., 2011; Yang et al., 2003). R614C has also been classified as pathogenic multiple times in the RYR1 Leiden Open Variation Database (LOVD) and the ClinVar database. Additionally, different missense variants at the same position (R614L) and in a nearby residue (A612T) have been reported in the Human Gene Mutation Database in association with malignant hyperthermia (Quane et al., 1997; Stenson et al., 2014; Tong et al., 1997; Tong et al., 1999). R614C was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R614C pathogenic variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Based on the ACMG recommendations, R614C is interpreted as a known pathogenic sequence change.