Adaptation of ACMG/AMP Guidelines for Clinical Classification of BMPR2 Variants in Pulmonary Arterial Hypertension Resolves Variants of Unclear Pathogenicity in ClinVar

• Published in: Human mutation Vol. 2025; no. 1; p. 2475635
• Main Authors: Eichstaedt, Christina A., Maldonado-Velez, Gabriel, Machado, Rajiv D., Gräf, Stefan, Dooijes, Dennis, Balachandar, Srimmitha, Coulet, Florence, Day, Kristina, Eyries, Melanie, Macaya, Daniela, Shaukat, Memoona, Southgate, Laura, Tenorio-Castano, Jair, Chung, Wendy K., Welch, Carrie L., Aldred, Micheala A.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.01.2025; Wiley
• Subjects: Bone morphogenetic protein receptor type II; Bone Morphogenetic Protein Receptors, Type II - genetics; Cardiac catheterization; Cardiovascular disease; Congenital diseases; Family medical history; FDA approval; Genes; Genetic Predisposition to Disease; Genetic Variation; Genetics; Genomes; Genomics; Heart; Humans; Hypertension, Pulmonary - genetics; Intubation; Kinases; Mutation; Pathogenicity; Practice Guidelines as Topic; Pulmonary Arterial Hypertension - diagnosis; Pulmonary Arterial Hypertension - genetics; Pulmonary arteries; Pulmonary hypertension; RNA Splicing; Working groups; United States > US; ACMG/AMP guidelines; BMPR2; pulmonary arterial hypertension; ClinVar; variant interpretation
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1155/humu/2475635

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.