The APOB gene has been reported in association with hypercholesterolemia (autosomal dominant) and hypobetalipoproteinemia (autosomal recessive). The relationship between APOB and hypercholesterolemia (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework. Variants in APOB were first reported in humans with hypercholesterolemia as early as 1989 (Soria et al., PMID: 2563166). At least 7 variants (missense) in at least 13 probands in 6 publications been reported in humans (PMIDs: 24498611, 24234650, 15135245, 22408029, 2563166, 7627691). Variants in this gene segregated with disease in at least 41 family members. This gene-disease relationship has been studied in at least 1 case-control study at the single variant level with an odds ratio of 78 (95% CI 16-388, p=0.0001) (PMID: 9603795). The mechanism for disease involves mainly heterozygous missense variants resulting in defective apo B100 on LDL particles that fails to bind to LDLR (PMID: 29219151). The gene-disease association is also supported by in vitro studies and animal models. In summary, APOB is definitively associated with autosomal dominant hypercholesterolemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Gene Curation EP on 11/14/2018.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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