Clinical Domain Working Groups

We are specifically setting out to tackle the problem of RYR1 and CACNA1S variants associated with malignant hyperthermia. We plan to evaluate evidence for variants that have an assertion of causality for MHS (typically dominant gain of function) and have excluded those with assertions for myopathy (typically recessive loss of function). We believe that this limitation of scope (i.e., not including RYR1 variants is necessary and appropriate, given that the state of the art in the field suggests that MHS arises through a gain of function mechanism and is inherited in an autosomal dominant pattern, whereas RYR1-related myopathy is thought to be a loss of function (or hypomorphic) mechanism and is inherited in an autosomal recessive pattern.