Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment

Ann Hum Genet. 2012 Sep;76(5):387-401. doi: 10.1111/j.1469-1809.2012.00724.x.


Familial hypercholesterolemia (FH) is caused predominately by variants in the low-density lipoprotein receptor gene (LDLR). We report here an update of the UCL LDLR variant database to include variants reported in the literature and in-house between 2008 and 2010, transfer of the database to LOVDv.2.0 platform (https://grenada.lumc.nl/LOVD2/UCL-Heart/home.php?select_db=LDLR) and pathogenicity analysis. The database now contains over 1288 different variants reported in FH patients: 55% exonic substitutions, 22% exonic small rearrangements (<100 bp), 11% large rearrangements (>100 bp), 2% promoter variants, 10% intronic variants and 1 variant in the 3' untranslated sequence. The distribution and type of newly reported variants closely matches that of the 2008 database, and we have used these variants (n= 223) as a representative sample to assess the utility of standard open access software (PolyPhen, SIFT, refined SIFT, Neural Network Splice Site Prediction Tool, SplicePort and NetGene2) and additional analyses (Single Amino Acid Polymorphism database, analysis of conservation and structure and Mutation Taster) for pathogenicity prediction. In combination, these techniques have enabled us to assign with confidence pathogenic predictions to 8/8 in-frame small rearrangements and 8/9 missense substitutions with previously discordant results from PolyPhen and SIFT analysis. Overall, we conclude that 79% of the reported variants are likely to be disease causing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Databases as Topic*
  • Genetic Variation*
  • Humans
  • Hyperlipoproteinemia Type II / genetics*
  • Mutation
  • Protein Isoforms
  • Receptors, LDL / genetics*


  • Protein Isoforms
  • Receptors, LDL