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

• Published in: Journal of medical genetics Vol. 54; no. 4; p. 217
• Main Authors: Leigh, Sarah, Futema, Marta, Whittall, Ros, Taylor-Beadling, Alison, Williams, Maggie, den Dunnen, Johan T, Humphries, Steve E
• Format: Journal Article
• Language: English
• Published: England 01-04-2017
• Subjects: Databases, Genetic; Genetic Variation; Humans; Hyperlipoproteinemia Type II - genetics; Hyperlipoproteinemia Type II - pathology; Mutation, Missense - genetics; Phenotype; Promoter Regions, Genetic; Receptors, LDL - genetics; database; locus specific variant; LDLR; Familial Hypercholesterolemia; in silico pathogenicity predictions
• ISSN: 1468-6244
• DOI: 10.1136/jmedgenet-2016-104054

Familial hypercholesterolaemia (OMIM 143890) is most frequently caused by variations in the low-density lipoprotein receptor (
) 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)
variant database according to these guidelines.
PubMed searches and alerts were used to identify novel
variants for inclusion in the database. Standard
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.
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.
This study updates the
variant database and identifies a number of reported VUS where additional family and
studies will be required to confirm or refute their pathogenicity.