A toxic gain-of-function variant confers a new, harmful activity or an excess of the protein’s normal activity, rather than losing function. It includes neomorphic activity (a novel activity such as toxic aggregation), overactivity (more of the normal activity), gene-dosage excess (too many copies), and pathogenic repeat expansions. Because the harm comes from the mutant protein itself, adding back wild-type protein does not rescue. In CMT, the PMP22 duplication that causes CMT1A is a gene-dosage gain of function.
See how the toxic gain-of-function call is applied across subtypes in the CMT Variant Mechanisms Browser.
