ENG p.Cys382Tyr

The NM_001114753.3: c.1145G>A variant in ENG is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 382 (p.Cys382Tyr). This variant alters amino acid C382 of ENG that is defined as a critical residue (previously reported to be likely pathogenic or pathogenic) by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM1; PMID: 17786384). This variant has been reported in more than 4 probands with a phenotype consistent with 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; PMID: 30763665). The variant has been reported to segregate with HHT in 3 affected family members from a single family (PP1; PMID: 30763665, Internal lab contributors). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.56, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. Functional assays showed the variant protein to have reduced protein expression in CHO-K1 cells, indicating that this variant impacts protein function (PS3_Supporting, PMID: 30763665). In summary, this variant meets the criteria to be classified as 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, PM1, PP4_Moderate, PM2_Supporting, PS3_Supporting, PP1 (specifications version 1.1.0; 02/04/2025).