The UCL low-density lipoprotein receptor gene variant database: pathogenicity update

2016/11/07 by S. E. A. Leigh, Sarah Leigh, Marta Futema +8 · 116 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Bioinformatics #Biology #Computational biology #Computer science #Database #Diabetes, Cardiovascular Risks, and Lipoproteins #Gene #Genetics #Genomics and Rare Diseases #In silico #LDL receptor #Lipoprotein #Lipoproteins and Cardiovascular Health #Missense mutation #Mutation #Nonsense #Pathogenicity

paper · pdf · doi:10.1136/jmedgenet-2016-104054

published in Journal of Medical Genetics 54(4), 217-223 (BMJ)

openalex publication_date 2016/11/07 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/05

Abstract

Background Familial hypercholesterolaemia (OMIM 143890) is most frequently caused by variations in the low-density lipoprotein receptor ( LDLR ) gene. Predicting whether novel variants are pathogenic may not be straightforward, especially for missense and synonymous variants. In 2013, the Association of Clinical Genetic Scientists published guidelines for the classification of variants, with categories 1 and 2 representing clearly not or unlikely pathogenic, respectively, 3 representing variants of unknown significance (VUS), and 4 and 5 representing likely to be or clearly pathogenic, respectively. Here, we update the University College London (UCL) LDLR variant database according to these guidelines. Methods PubMed searches and alerts were used to identify novel LDLR variants for inclusion in the database. Standard in silico tools were used to predict potential pathogenicity. Variants were designated as class 4/5 only when the predictions from the different programs were concordant and as class 3 when predictions were discordant. Results The updated database ( http://www.lovd.nl/LDLR ) now includes 2925 curated variants, representing 1707 independent events. All 129 nonsense variants, 337 small frame-shifting and 117/118 large rearrangements were classified as 4 or 5. Of the 795 missense variants, 115 were in classes 1 and 2, 605 in class 4 and 75 in class 3. 111/181 intronic variants, 4/34 synonymous variants and 14/37 promoter variants were assigned to classes 4 or 5. Overall, 112 (7%) of reported variants were class 3. Conclusions This study updates the LDLR variant database and identifies a number of reported VUS where additional family and in vitro studies will be required to confirm or refute their pathogenicity.

Citations

• Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic

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