ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.