ACVRL1

Inheritance Pattern: AD

Disease ID:MONDO:0010880

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0019180

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0010880

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0019180

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0010880

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0010880

Submitter: ClinGen

The relationship between *ACVRL1* and hereditary hemorrhagic telangiectasia, type 2 (HHT2), an autosomal dominant disorder, was evaluated using the ClinGen Clinical Validity Framework as of April 1, 2019. *ACVRL1* was first reported in relation to HHT2 in 1996 (Johnson et al., PMID: 8640225). HHT2 is evaluated by the presence of 3 or more of the Curacao criteria (PMID: 10751092). ACVRL1 is a type I TGF-β receptor and interacts with ENG in the TGF-β pathway. ENG is known to cause HHT1. The mechanism for disease is haploinsufficiency (PMID: 15879500) and at least 571 ACVRL1 variants, ranging from missense, in-frame indel to nonsense, frameshift, large deletions and whole gene deletions, have been reported in humans (http://www.arup.utah.edu/database/ACVRL1/ACVRL1_welcome.php). Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Variants included in this curation come from 13 probands in 6 publications (PMIDs 86402252, 17384219, 26176610, 9245985 20364125, 20414677) and segregated with disease in 12 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence evidence (12 pts) has been reached. This gene-disease relationship is also supported by animal models and in vitro functional assays. A number of mouse and zebra fish models have been developed for HHT (PMID: 17911384, 12588795, 24896812, 12050147). Additionally, interaction with the HHT-related gene *ENG* in the TGF-β pathway has been experimentally demonstrated (PMID: 15702480, 12015308). In summary, *ACVRL1* is definitively associated with autosomal dominant hereditary hemorrhagic telangiectasia, Type 2. 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 Hemostasis/Thrombosis Gene Curation Expert Panel on August 28, 2019 (SOP Version 6). Scoring was updated on 11/29/2022. Of note, pulmonary arterial hypertension (PAH) is a rare but severe complication of HHT2 that was independently evaluated as of June 9, 2021 by the Pulmonary Hypertension GCEP. More than 22 probands with rare, predicted deleterious *ACVRL1* variants have been reported (PMIDs:11484689, 14684682, 15065824, 20056902, 31727138 and others). Multiple variant types, including missense, have been reported and the carboxy terminus contains a conserved 11 amino acid NANDOR box in the protein kinase domain that shows enrichment of rare missense variants among PAH-HHT cases compared to HHT alone (PMID:20056902). Experimental evidence for a gene-disease relationship for HHT-PAH includes expression in pulmonary arterial endothelial cells and PAH plexiform lesions (PMID: 11484689), interaction with receptor ligand BMP10 (PMID: 17068149), and spontaneous pulmonary hypertension in an Acvrl1 knockout HHT mouse model (PMID: 21859819).

Inheritance Pattern: AD

Disease ID:MONDO:0010880

Submitter: Labcorp Genetics (formerly Invitae)