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.
- Familial Hypercholesterolemia
- locus specific variant
- in silico pathogenicity predictions
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Contributors SL: principal in collation and analysis of variants, and of manuscript preparation; MF: collation and analysis of variants, contributor in manuscript preparation; RW: collation and analysis of variants; AT-B, MW: clinical contribution of novel variants and knowledge regarding significance of variants to patients; JTdD: responsible for formatting data to be loaded onto the LOVD platform and responsible for maintenance and development of this database platform; SEH: project lead, giving direct guidance, advice and support for the study and assistance in manuscript preparation.
Funding British Heart Foundation BHF PG08/008.
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.
Provenance and peer review Not commissioned; externally peer reviewed.
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