ClinVar

Description

The p.Ser1728Phe variant in RYR1 has been reported in at least 8 individuals with malignant hyperthermia susceptibility (MH) and segregated with disease in 6 affected family members (Robinson 2006 PMID:16917943, Dalton 2007 (thesis), Carpenter 2009 PMID 19648156, Miller 2018 PMID 30236257). In one family, it was reported not to segregate clearly with disease (with phenotyping based on in vitro contracture tests; IVCT) but no specific details were provided (Miller 2018 PMID 30236257). In addition, it has been reported at least 1 individual with no personal or family history of MH (Gonsalves 2013 PMID 24195946), was identified in 1/34500 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org/) and has also been reported in ClinVar (Variation ID 133144). Notably, IVCT performed on muscle tissue from individuals carrying this variant suggest that the p.Ser1728Phe variant may be associated with weaker MH phenotypes (Carpenter 2009 PMID 19648156). Computational prediction tools and conservation analysis suggest that the variant may not impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant MH with a less severe phenotype than other disease causing RYR1 variants. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP1_Moderate, PS3_Moderate, BP4.