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. 2017 Apr;54(4):217-223.
doi: 10.1136/jmedgenet-2016-104054. Epub 2016 Nov 7.

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

Sarah Leigh  1 , Marta Futema  1 , Ros Whittall  1 , Alison Taylor-Beadling  2 , Maggie Williams  3 , Johan T den Dunnen  4 , Steve E Humphries  1
Affiliations

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

Sarah Leigh et al. J Med Genet. 2017 Apr.

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.

Keywords: Familial Hypercholesterolemia; LDLR; database; in silico pathogenicity predictions; locus specific variant.

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Conflict of interest statement

Competing interests: SEH holds a chair funded by the British Heart Foundation, and SEH and RW are supported by the BHF (PG08/008) and by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. MF is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.

Figures

Figure 1
Figure 1
A summary of pathogenicity classifications for each variant category. The percentage of variants in each of the outlined categories according to their pathogenicity classification is shown. fs, frame-shifting; LDLR, low-density lipoprotein receptor; lrg, large; smll, small.
See this image and copyright information in PMC

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