Christina A. Eichstaedt, Gabriel Maldonado-Velez, Rajiv D. Machado, Stefan Gräf, Dennis Dooijes, Srimmitha Balachandar, Florence Coulet,
Kristina Day, Melanie Eyries, Daniela Macaya, Memoona Shaukat, Laura Southgate, Jair Tenorio-Castano, Wendy K. Chung, Carrie L. Welch,
Micheala A. Aldred
Thoraxklinik-Heidelberg gGmbH, Heidelberg University Hospital and Translational Lung Research Center (TLRC), German Center for Lung Research (DZL). Indiana University School of Medicine. University of London. University of Cambridge. University Medical Centre Utrecht and Utrecht University. Sorbonne University. GeneDx Inc. La Paz University Hospital, IDiPAZ and Autonoma University of Madrid. Carlos III Health Institute. European Reference Network. Boston Children’s Hospital and Harvard Medical School.
Germany, United States, United Kingdom, Netherlands, France, Spain and Belgium
Human Mutation
Hum Mutat 2025;
DOI: 10.1155/humu/2475635
Abstract
Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by pathogenic variants, most frequently in the bone Morphogenetic Protein Receptor Type 2 (BMPR2) gene. We formed a ClinGen variant curation expert panel to devise guidelines for the clinical interpretation of BMPR2 variants identified in PAH patients. The general ACMG/AMP variant classification criteria were refined for PAH and adapted to BMPR2 following ClinGen procedures. Subsequently, these specifications were tested independently by three members of the curation expert panel on 28 representative BMPR2 variants selected from ClinVar and then presented and discussed in the plenum. Application of the final BMPR2 variant specifications resolved six of nine variants (66%) where multiple ClinVar classifications included a variant of uncertain significance, with all six being reclassified as Benign or Likely Benign. Four splice site variants underwent clinically consequential reclassification based on the presence or absence of supporting mRNA splicing data. These variant specifications provide an international framework and a valuable tool for BMPR2 variant classification that can be applied to increase confidence and consistency in BMPR2 interpretation for diagnostic laboratories, clinical providers, and patients.
Category
Genetic Factors Associated with Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease and Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes