ANGPT1

Inheritance Pattern: Unknown

Disease ID:MONDO:0030293

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0030293

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0005041

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0000365

Submitter: ClinGen

*ANGPT1* was first reported in relation to autosomal dominant primary congenital glaucoma in 2017 (Thompson et al., PMID: 29106382). Primary congenital glaucoma is a condition with an onset before 3 years of age that is identified by increased intraocular pressure, an enlarged ocular globe, increased corneal diameter and corneal edema. Angiopoietin 1, the *ANGPT1* protein, is a angiogenic growth factor that was shown by Thomson et al. to be essential as a TEK ligand in the development of Schlemm’s canal. At least five variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in *ANGPT1* have been reported in individuals with both primary congenital glaucoma and hereditary angioedema. These two entities have distinct phenotypic variability with no reported or known overlap between the two phenotypes, even though the two assertions have the same inheritance pattern and loss of function as a suspected molecular mechanism. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, the following disease entities have been split into two disease entities, primary congenital glaucoma (OMIM:231300) and hereditary angioedema (OMIM:619361). Four variants (nonsense, missense) in this gene have been reported in at least four probands in two publications (PMID: 29106382, 36995002). At least one more variant in this gene has been identified in a GWAS study to be significantly associated with elevated intraocular pressure, which is correlated with the development of glaucoma, but is not included in this curation (PMID: 29785010). Only nonsense variants were given scores above 0 in this curation; two missense variants are reported in the curation, one carrying variant alleles in two other genes already established by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel to have a definitive relationship to primary congenital glaucoma and one with function evidence that shows the ability of the missense variant protein to interact with its receptor. The two nonsense variants scored in this curation have functional evidence supporting their scores that show that they may diminish TEK activation through oligomerization with the wild type protein. There are unpublished cases of primary congenital glaucoma due to *ANGPT1* that could not be scored in the curation; additional published cases would be valuable in increasing the classification of this gene-disease relationship. This gene-disease relationship is supported by two mouse models showing the correlation of *ANGPT1* with development of glaucoma. Thomson et al. used a conditional gene knockout to show that mice without functional angiopoietin 1 demonstrate hypomorphic Schlemm’s canal, which is insufficient for normal aqueous humor drainage, with clinical signs of glaucoma including increased IOP and decreased retinal ganglion cells as compared to control mice. In the same publication, the authors reiterated this with a functionally null variant of *ANGPT1*, p.R494Ter, which showed that the variant could not replace wilde type in the as the conditional knockout mice (PMID:29106382). The Thomson *ANGPT1* conditional knockout mouse was published again as a genetic model of high pressure glaucoma resource for other investigators in 2020 (PMID:32818103). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on February 15th, 2024 (SOP Version 10).