The relationship between ANGPTL3 and familial hypobetalipoproteinemia 2 inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of July, 2022. This association was made using case-level and experimental data. Familial hypobetalipoproteinemia 2 is characterized by a combined deficiency of plasma lipids: very low VLDL, LDL, and HDL levels, and consequently low total TG and cholesterol levels (PMID: 26754661). The ANGPTL3 gene encodes a member of a family of secreted proteins that function in lipid metabolism and angiogenesis.
Summary of Case Level Data (12 points): The association is seen in at least 7 probands with mostly predicted or established loss-of-function variants in 5 publications (PMID: 22155345, 22659251, 20942659, 22247256, 22062970). Variants in this gene segregated with disease in 34 additional family members (PMID: 20942659). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached.
The mechanism for disease is biallelic loss of function. Some heterozygous carriers are occasionally noted to have plasma lipid levels in the disease range; however, most carriers have plasma lipid levels in the normal range. Only individuals with biallelic variants were scored for this curation.
Summary of Experimental Data (6 points): The ANGPTL3 protein is almost exclusively expressed in the liver (PMID: 11788823). Mouse and zebrafish models with ANGPTL3 alterations recapitulate the human hypobetalipoproteinemia phenotype (PMID: 11788823, 24685482). Introduction of WT gene into the Angptl3-/- mouse model restores lipid levels (PMID: 11788823). In-vitro functional assays elucidate the role of ANGPTL3 mutations in disease, which acts through reversible inhibition of LPL (PMID: 12097324, 26754661, 19028676). ANGPTL3 is a therapeutic target to lower lipid levels in dyslipidemia, and studies have been conducted in mice, monkeys and humans (PMID: 25964512, 28538111)
In summary, the ANGPTL3-Familial Hypobetalipoproteinemia 2 gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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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