PCSK9 and familial hypercholesterolemia: While there is evidence that the S127R mutation enhances PCSK9’s ability to bind LDLR and induce LDLR degradation in cells, this effect is modest compared to the D374Y mutation (Figure 3B) (Cunningham et al., 2007; Pandit et al., 2008; Martin et al., 2020) and thus unlikely to account for severe hypercholesterolemia in S127R patients.