Table 2.

Gain-of-function mutations.

Name of Mutation + Reference	Cause and Consequences
Arg499His [135] Arg496Trp [136] Asp129Gly [23]	Variations in C-terminal domain that drive the intracellular degradation of LDLR
Asp374His [23] E32K (Leu108Arg) [23] D374H [137,138]	Causes increased binding affinity to LDLR and hypercholesterolaemia
Asp374Tyr [103,136]	Mutation in the catalytic domain that improves the interaction of PCSK9 with the EGF-A domain of LDLR
Asp35Tyr [23]	Mutation that creates a novel Tyr-sulfation site to enhance the intracellular activity of PCSK9
D129G [103]	Mutation in pro-domain that leads to faster protein mobility from ER to Golgi faster in comparison to normal PCSK9
D374Y (rs137852912) [103,104,126,137,139,140] R496W (rs374603772) [104]	Causes 10–25-fold higher binding capacity to LDLR causing early CAD, atherosclerosis
D377Y [19]	Causes abdominal aortic aneurysm
Phe216Leu [99]	Decreases the circulating LDLR levels due to its destruction with the help of PCSK9 intracellularly
R215H [119] F216L [137,141] R218S [105]	SNPs that abolish furin cleavage
R357H [142]	Mutation in catalytic domain that leads to hypercholesterolaemia
R496Q [126]	Leads to hyperlipoproteinaemia
S386A [141] F216L [104,137,141]	Increases secretion of ApoB100-containing lipoproteins
S127R (rs28942111) [103,104,115,118,137,143,144]	Mutation in pro-domain that leads to increased binding affinity of PCSK9 to VLDLR and high circulating levels of VLDL, IDL and ApoB100-containing lipoproteins
Ser127Arg [136]	Variation in pro-domain that improves the chance of preventing LDLR from entering a closed conformation