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Familial Hypercholesterolemia (FH) is a common genetic disorder caused most often by mutations in the Low Density Lipoprotein Receptor gene ( LDLr ) leading to high blood cholesterol levels, and ultimately to development of premature coronary heart disease. Genetic analysis and subsequent cascade screening in relatives allow diagnosis of FH at early stage, especially relevant to diagnose children. So far, more than 2300 LDLr variants have been described but only a minority of them have been functionally analysed to evaluate their pathogenicity in FH. Thus, identifying pathogenic mutations in LDLr is a long-standing challenge in the field. In this study, we investigated  in vitro  the activity p.(Asp47Asn) and p.(Thr62Met)  LDLr  variants, both in the LR1 region. We used CHO- ldlA7  transfected cells with plasmids carrying p.(Asp47Asn) or p.(Thr62Met)  LDLr  variants to analyse LDLr expression by FACS and immunoblotting, LDL binding and uptake was determined by FACS and analysis of mutation effects was assessed  in silico . The  in vitro  activity assessment of p.(Asp47Asn) and p.(Thr62Met)  LDLr  variants shows a fully functional LDL binding and uptake activities. Therefore indicating that the three of them are non-pathogenic LDLr variants. These findings also emphasize the importance of  in vitro  functional LDLr activity studies to optimize the genetic diagnosis of FH avoiding the report of non-pathogenic variants and possible misdiagnose in relatives if cascade screening is carried out.

p.(Asp47Asn) and p.(Thr62Met): non deleterious LDL receptor missense variants functionally characterized in vitro