uAUG-creating variant in the LDLR gene causes mild Familial hypercholesterolemia

Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein (LDL) levels, leading to early-onset cardiovascular disease. FH is primarily caused by pathogenic variants in the LDLR gene, affecting cholesterol metabolism. We describe a family with a mild form of FH, in which gene panel sequencing identified a novel c.-8C>A variant in the LDLR 5'UTR. To assess its functional impact, we performed a luciferase assay and found that this variant partially reduces LDLR protein translation efficiency by introducing a novel upstream AUG (uAUG) start codon. This partial reduction in LDLR activity is consistent with the mild phenotype observed in the family. Additionally, we analyzed three previously reported LDLR 5'UTR variants (c.-5C>T, c.-14C>A, and c.-23A>C) but did not observe any significant effect on LDLR expression, suggesting that these variants are unlikely to contribute to disease development. These findings highlight the role of 5'UTR variants in LDLR expression and emphasize the importance of functional studies in variant classification for FH diagnostics.