Clinical Domain Working Groups

Pathogenic germline variants in ACVRL1, ENG, and SMAD4 are associated with hereditary hemorrhagic telangiectasia (HHT, MIM: 600376, 187300) and juvenile polyposis syndrome/HHT (JPS/HHT, MIM: 175050). HHT is an autosomal dominant vascular dysplasia characterized by small vascular lesions (telangiectases) and larger vascular lesions (arteriovenous malformations (AVMs)) in characteristic locations (telangiectases in the oral and nasal mucosa, lips, fingers, upper intestinal tract; AVMs in the lungs, liver and brain). This expert panel will provide assessment regarding the pathogenicity of variants in ACVRL1, ENG, and SMAD4 with respect to HHT disease. Specifically, we will develop a set of HHT rule specifications of the ACMG/AMP guidelines with individual gene specifications where needed. We will first focus our efforts on curating variants that are currently in ClinVar, and then we will expand our efforts to curating variants from other HHT databases and submit those to ClinVar.

Step 3 Approvals:

• September 1, 2023 - VCEP received approval for ACMG/AMP specifications ACVRL1 and ENG