The NM_001114753.3: c.1645T>G variant in ENG is a missense variant predicted to cause substitution of cysteine by glycine at amino acid 549 (p.Cys549Gly). This variant has been reported in 3 probands with a phenotype consistent with Hereditary Hemorrhagic Telangiectasia (PS4_Moderate, Internal lab contributors, Invitae, Victorian Clinical Genetics Service). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.861 which is above the threshold of 0.644, evidence that correlates with impact to ENG function (PP3). Another missense variant c.1646G>A, p.Cys549Tyr (PMIDs: 38828001, 20414677, 21158752; ClinVar Variation ID: 407135) in the same codon has been classified as pathogenic for Hereditary Hemorrhagic Telangiectasia by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM5). This variant resides within a region, amino acid C549, of ENG that is defined as a mutational hotspot or critical functional domain by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PMIDs: 28564608, 25312062) (PM1). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS4_Moderate, PM2_Supporting, PP3, PM5, PM1 (specifications version 1.1.0; 09/11/2024).