ENG

Gene Facts

• HGNC Symbol: ENG (HGNC:3349)
• HGNC Name: endoglin
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: ORW1, ORW
• Alias symbols: END, HHT1, CD105
• %HI: 23.71
• pLI: 1
• LOEUF: 0.37
• Cytoband: 9q34.11
• Genomic Coordinates:

  GRCh37/hg19:	chr9:130577291-130617052
  GRCh38/hg38:	chr9:127815016-127854658

• MANE Select Transcript: NM_001114753.3 ENST00000373203.9
• Function: Vascular endothelium glycoprotein that plays an important role in the regulation of angiogenesis (PubMed:21737454, PubMed:23300529). Required for normal structure and integrity of adult vasculature (PubMed:7894484). Regulates the migration of vascular endothelial cells (PubMed:17540773). Required for normal extraembryonic angiogenesis and for embryonic heart development (By similarity). May regulate endothelial cell shape changes in response to blood flow, which drive vascular remodeling and est... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-5892
• ClinGen Curation ID: CCID:007070
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 01/11/2024

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• Hereditary Hemorrhagic Telangiectasia, type 1

HI Evidence

• PUBMED: 9245986
  ENG sequencing analysis was carried out in 28 families with the clinical diagnosis of Hereditary Hemorrhagic Telangiectasia (HHT) (total 32 families were enrolled in the study). Six are predicted be loss-of-function variants and the other is a 21-bp in-frame deletion in the exon 5. The loss-of-function variants are: ~1.5 kb deletion spanning exon 8, a deletion spanning exon 9 – exon 14, an 152-bp deletion in exon 2, a canonical splice donor site variant of intron 8, a canonical splice donor site variant in intron 3 and a gain of stop codon in exon 4. mRNA sequencing showed an either depleted mutant allele or altered mRNA predicted to yield a markedly truncated ENG protein. These data suggest a haploinsufficiency mechanism of ENG mutations.
• PUBMED: 9366572; 10545596; 10749981
  Protein expression analysis using quantitative flow cytometry, metabolic labeling and immunoprecipitation for a mutant with an in-frame deletion of exon 3 demonstrated a ~50% of normal dimeric endoglin (160 KD) expression on the cell surface while mutant protein can only be detected as an intracellular homodimer of 130 KD. Two mutants with premature stop codon in exon 8 and 10 also demonstrated a reduced (~50%) normal cell surface endoglin and no mutant protein was detected on the cell surface. Over expression of truncated cDNA showed it’s inability to be secreted and to form heterodimers at the cell surface. Missense variants also demonstrated a non-expression of mutant protein on cell surface. Theses functional studies are consistent with a haploinsufficiency mechanism of ENG mutations. However, Lux et al. demonstrated that certain mutants (missense and frameshift) are able to form a heterodimer with the normal protein and being able to be trafficked to cell surface suggesting a dominant negative mechanism in addition to haploinsufficiency.
• PUBMED: 15879500
  Abdalla et al. summarized 155 published ENG mutations. The mutations include deletions (n= 51), missense (n= 31), splice sites (n = 21), insertions (n = 25), nonsense (n = 23), indels (n = 4). 115 mutations are predicted to be loss-of-function variants.
• PUBMED: 23399955; 35487791
  603 patients with 5 or more gastrointestinal polyps, including at least 1 harmatomatous or hyperplastic/serrated polyp were screened for germline mutations in PTEN, BMPR1A, SMAD4, ENG an STK11 genes. Seventy-seven patients (13%) were found to have mutations in one of the genes. 11 patients were found to harbor mutations in the ENG gene (1.8%). Mutations in ENG gene are all missense variant (c.572G>A, p.Gly191Asp variant was detected in several families). Mutations were classified based on previous reported in literatures or database. No functional studies were carried out. Currently there is no definitive information on the risk of gastrointestinal hamartomatous polyposis conferred by HHT mutations.

• HI Evidence Comments: Numerous loss-of-function mutations had been reported in HHT patients and functional analyses support a haploinsufficiency of the ENG gene.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: No duplication solely involving ENG gene has bee reported