. 2025 Jul 6:2025:2475635.

doi: 10.1155/humu/2475635. eCollection 2025.

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

Christina A Eichstaedt^{1

2}, Gabriel Maldonado-Velez³, Rajiv D Machado⁴, Stefan Gräf⁵, Dennis Dooijes⁶, Srimmitha Balachandar³, Florence Coulet^{7

8}, Kristina Day³, Melanie Eyries⁸, Daniela Macaya⁹, Memoona Shaukat^{1

2}, Laura Southgate⁴, Jair Tenorio-Castano^{10

11

12}, Wendy K Chung¹³, Carrie L Welch¹³, Micheala A Aldred³

Affiliations

¹ Center for Pulmonary Hypertension, Thoraxklinik-Heidelberg gGmbH, Heidelberg University Hospital and Translational Lung Research Center (TLRC), German Center for Lung Research (DZL), Heidelberg, Baden-Württemberg, Germany.
² Laboratory for Molecular Genetic Diagnostics, Institute of Human Genetics, Heidelberg University, Heidelberg, Baden-Württemberg, Germany.
³ Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁴ School of Health & Medical Sciences, City St George's, University of London, London, UK.
⁵ Department of Medicine, School of Clinical Medicine, University of Cambridge, Victor Phillip Dahdaleh Heart & Lung Research Institute, Cambridge, UK.
⁶ Department of Genetics, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands.
⁷ Saint-Antoine Research Centre, Sorbonne University, Paris, France.
⁸ Genetics Department, AP-HP Sorbonne University, Paris, France.
⁹ GeneDx Inc., Gaithersburg, Maryland, USA.
¹⁰ Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, IDiPAZ, Autonoma University of Madrid, Madrid, Spain.
¹¹ Biomedical Research Network Centre for Rare Diseases (CIBERER), Carlos III Health Institute, Madrid, Spain.
¹² ITHACA, European Reference Network, Brussels, Belgium.
¹³ Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

PMID: 40661831
PMCID: PMC12256177
DOI: 10.1155/humu/2475635

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

Christina A Eichstaedt et al. Hum Mutat. 2025.

. 2025 Jul 6:2025:2475635.

doi: 10.1155/humu/2475635. eCollection 2025.

Authors

Affiliations

¹ Center for Pulmonary Hypertension, Thoraxklinik-Heidelberg gGmbH, Heidelberg University Hospital and Translational Lung Research Center (TLRC), German Center for Lung Research (DZL), Heidelberg, Baden-Württemberg, Germany.
² Laboratory for Molecular Genetic Diagnostics, Institute of Human Genetics, Heidelberg University, Heidelberg, Baden-Württemberg, Germany.
³ Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁴ School of Health & Medical Sciences, City St George's, University of London, London, UK.
⁵ Department of Medicine, School of Clinical Medicine, University of Cambridge, Victor Phillip Dahdaleh Heart & Lung Research Institute, Cambridge, UK.
⁶ Department of Genetics, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands.
⁷ Saint-Antoine Research Centre, Sorbonne University, Paris, France.
⁸ Genetics Department, AP-HP Sorbonne University, Paris, France.
⁹ GeneDx Inc., Gaithersburg, Maryland, USA.
¹⁰ Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, IDiPAZ, Autonoma University of Madrid, Madrid, Spain.
¹¹ Biomedical Research Network Centre for Rare Diseases (CIBERER), Carlos III Health Institute, Madrid, Spain.
¹² ITHACA, European Reference Network, Brussels, Belgium.
¹³ Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

PMID: 40661831
PMCID: PMC12256177
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.

Keywords: ACMG/AMP guidelines; BMPR2; ClinVar; pulmonary arterial hypertension; variant interpretation.

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Conflict of interest statement

CAE received honoraria for lectures and presentations from OMT and MSD, consulting fees from MSD. CAE is coinventor of the issued European patent “Gene panel specific for pulmonary hypertension and its uses” (EP3507380). CAE works at a laboratory that performs fee for service testing in genes that have been specified by the ClinGen PH VCEP. FC works at a French healthcare hospital (Pitié-Salpêtrière Hospital in Paris) laboratory which performs noncommercial fee for service testing in BMPR2 and other PAH genes. DD works at a Dutch healthcare hospital laboratory which performs noncommercial fee for service testing in BMPR2 and other PAH genes. ME worked at a French healthcare hospital laboratory which performs noncommercial fee for service testing in BMPR2 and other PAH genes. DM works for GeneDx, a laboratory that performs fee for service genetic testing. WKC serves on the Board of Directors of Prime Medicine. GMV and SB were graduate students at the time the study was performed but are now employed by fee for service genetic testing companies, Tempus and Baylor Genetics, respectively. MAA, SB, KMD, and GMV received salary support from the National Institutes of Health. All other authors declare no conflict of interest.

Figures

**Figure 1**
Flow chart of pulmonary hypertension variant curation expert panel formation and activities.

**Figure 2**
Comparison of ClinVar and PH VCEP classifications. Sankey plot shows the effect of applying our VCEP variant specifications (right) compared with the original ClinVar classification(s) (left) for the pilot panel of 28 *BMPR2* variants. P, pathogenic; LP, likely pathogenic; VUS, variant of uncertain significance; LB, likely benign; B, benign.

See this image and copyright information in PMC

Update of

Adaptation of ACMG/AMP guidelines for clinical classification of BMPR2 variants in Pulmonary Arterial Hypertension resolves variants of unclear pathogenicity in ClinVar.
Eichstaedt CA, Maldonado-Velez G, Machado RD, Balachandar S, Coulet F, Day K, Dooijes D, Eyries M, Gräf S, Macaya D, Shaukat M, Southgate L, Tenorio-Castano J, Chung WK, Welch CL, Aldred MA. Eichstaedt CA, et al. medRxiv [Preprint]. 2024 Nov 26:2024.11.24.24317862. doi: 10.1101/2024.11.24.24317862. medRxiv. 2024. Update in: Hum Mutat. 2025 Jul 6;2025:2475635. doi: 10.1155/humu/2475635. PMID: 39649591 Free PMC article. Updated. Preprint.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Update of

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Grants and funding

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Medical

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