ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 2q33.1-q33.2
  • GRCh37/hg19 chr2: 203,241,050-203,432,474
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr2: 202,376,310-202,567,751
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000002.11) (NC_000002.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
10903931 Deng et al. (2000) genotyped 35 multiplex families with primary pulmonary hypertension (PPH) using 27 microsatellite markers. BMPR2 was identified as a positional candidate, and analysis of BMPR2 coding sequence identified seven presumed disease-causative mutations in nine families. A premature stop codon in exon 4 (c.507?510delCTTTinsAAA; p.C169X) was identified in three affected individuals from family PPH017. DNA samples were available for six unaffected individuals from this family who were presumably mutation negative. Zero carriers were reported for this family, although it is unclear whether i) all mutation positive family members presented with PPH, or ii) if obligate carriers were not available for DNA sequence analysis. A stopgain mutation more than 55 nucleotides upstream of the exon-intron boundary of the penultimate exon 12 (c.2617C>T; p.R873X) was identified in three affected individuals and two carriers in family PPH018. A frameshift deletion in exon 12 (c.2579delT; p.N861fsX10) was identified in six affected individuals and one carrier from family PPH015.
11015450 Thomson et al. (2000) assessed 50 unrelated patients with a clinical diagnosis of primary pulmonary hypertension and no identifiable family history of disease for mutations in the coding sequence of BMPR2. De novo mutations in BMPR2 were identified in two patients, and included a frameshift deletion in exon 9 (c.1248delA), and a frameshift deletion occurring more than 55 nucleotides upstream of the exon-intron boundary of the penultimate exon 12 (c.2386delG). Paternity was confirmed in both families through the analysis of informative markers. Mutations resulting in a premature termination codon were identified in 8 additional patients (seven of unknown inheritance; one paternally transmitted). A nonsense mutation (R211X) was identified in a proband with primary pulmonary hyptertension and was not was not present in 150 normal chromosomes. Machado et al. (2001) identified the same mutation in 2 affected family members with PPH. Humbert et al. (2002; PMID:12358323) identified the same mutation in two sisters with PPH, and confirmed that the mutation was not present in 260 control chromosomes.
Loss PMID 3: 25612240 Momose et al. (2015) assessed the transmission of BMPR2 variants in families of 15 mutation-positive patients with pulmonary arterial hypertension. De novo mutations were confirmed in three probands from three separate families, and included a frameshift insertion in exon 2 (c.201insA), a mutation in the splice-acceptor site of exon 7 (c.853-2A>G) with functional analysis of patient mRNA confirming the presence of a transcript lacking exon 7, and an exon 10 deletion identified by MLPA analysis that is predicted to result in a frameshift and premature stop codon. Parental relationship was confirmed in all three families through analysis of informative STR markers.

Haploinsufficiency phenotype comments:

Additional information includes: From GeneReviews: BMPR2 mutations are identified in ~75% of cases with hereditary pulmonary arterial hypertension (formerly known as primary pulmonary hypertension). Incomplete penetrance of BMPR2 mutations is well-described, and penetrance is estimated as 0.2. Penetrance is sex dependent, and ranges from 0.14 in males to 0.48 in females. Over 600 disease-causative mutations in BMPR2 are documented in HGMD professional as of July 2020, and include 100 stopgain mutations, >100 small frameshift deletions/insertions, and >70 large exon-spanning deletions. A de novo whole gene deletion of BMPR2 has been identified in a proband by MLPA analysis (Aldred et al. 2006; subject ID 21646). However, as the upstream and downstream boundaries of the rearrangement were not characterized, the full extent of deleted sequence is unknown. PMIDs 11115378 and 16429395 provide an extensive list of mutations identified in cases of pulmonary arterial hypertension.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity