ClinVar Analysis of APOB Variants Associated with Familial Hypercholesterolemia

Ferreira, Maria Simões; Alves, Ana Catarina; Bourbon, Mafalda

http://hdl.handle.net/10400.18/8949

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Authors

Ferreira, Maria Simões

Alves, Ana Catarina

Bourbon, Mafalda

Abstract(s)

Familial hypercholesterolemia (FH) is an autosomal semi dominant disorder of lipid metabolism characterized by elevated LDL cholesterol levels associated with an increased cardiovascular risk. FH can be caused by variants in LDLR, APOB, and PCSK9 genes. Although most of the cases are due to variants in the LDLR gene, the APOB gene is responsible for 5-10% of the cases. The number of variants in this gene has been increasing due to Next Generation Sequencing; however, for most of these variants, their effect on the LDLR cycle is not known. The aim of this work was to evaluate the APOB variants reported in ClinVar associated with familial hypercholesterolemia. The ClinVar repository was consulted on May 2023 for this analysis, and all APOB variants submitted associated with FH were extracted. Variants submitted with no associated condition (“not specified”, “not provided”) or associated with other conditions (“Hypobetalipoproteinemia”, “Familial hypobetalipoproteinemia”, “Inborn genetic diseases”, “Cardiovascular phenotype”) were excluded. Information regarding classification, review status, and functional characterization was considered for this analysis A total of 2586 APOB variants were identified associated with FH, most of which were reported simultaneously with another condition. A total of 844 variants were submitted only associated to FH condition. From these, the majority were missense variants (592), followed by synonymous alterations (169); 38 frameshifts and nonsense variants were found. In terms of ClinVar classification, 18 were classified as pathogenic, 8 as likely pathogenic, and 234 as likely benign. The remaining were considered variants of uncertain significance (VUS) (566) or presented conflicting interpretations of pathogenicity (18). Most APOB variants (708) presented a review status of clinical significance corresponding to one star (one submitter or multiple submitters with conflicting interpretations of evidence), with only 121 variants presenting two stars (multiple submitters with the same interpretation of the evidence); 15 variants did not present any star (submission did not include evidence). The great majority of these variants lack functional studies proving their effect. The lack of evidence and knowledge about APOB variants compromises their correct classification and the diagnosis of FH, being crucial to share information regarding the variants between countries. Functional studies are very important to understand the effect of the variants in protein function and can contribute to changing a classification of VUS. It would be important develop specification for classification of APOB variants to for an accurate classification.