The NM_000020.3: c.998G>T variant in ACVRL1 is a missense variant predicted to cause substitution of serine by isoleucine at amino acid 333 (p.Ser333Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in >4 probands with a phenotype consistent of HHT (PS4; Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). The variant has been reported to segregate with disease in a large HHT family (PP1_Strong; Internal lab contributors). This variant resides within a region, Arg329-Asn335 (catalytic loop), of ACVRL1 that is defined as a critical functional domain/residue by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM1). The computational predictor REVEL gives a score of 0.975, which is above the threshold of ≥0.644, evidence that correlates with impact to ACVRL1 function (PP3). Additionally, western blot in HEK293T, COS7 and Hep3B mutant cells showed reduced surface expression of the variant protein and dominant-negative effect. Moreover, the variant induces embryonic dorsalization indicating that this variant impacts protein function (PS3_Supporting; PMID: 16282348). In summary, this variant meets the criteria to be classified as pathogenic for Hereditary Hemorrhagic Telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM1, PM2_Supporting, PS4, PS3_Supporting, PP1_Strong, PP3, PP4_Moderate (specification version 1.0.0; 1/04/2024).