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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

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...

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Main Authors: Eichstaedt, Christina (Author) , Maldonado-Velez, Gabriel (Author) , Machado, Rajiv D. (Author) , Gräf, Stefan (Author) , Dooijes, Dennis (Author) , Balachandar, Srimmitha (Author) , Coulet, Florence (Author) , Day, Kristina (Author) , Eyries, Melanie (Author) , Macaya, Daniela (Author) , Shaukat, Memoona (Author) , Southgate, Laura (Author) , Tenorio-Castano, Jair (Author) , Chung, Wendy K. (Author) , Welch, Carrie L. (Author) , Aldred, Micheala A. (Author)
Format: Article (Journal)
Language:English
Published: 2025
In: Human mutation
Year: 2025, Pages: 1-13
ISSN:1098-1004
DOI:10.1155/humu/2475635
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1155/humu/2475635
Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1155/humu/2475635
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Author Notes: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, and Micheala A. Aldred
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Summary: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.
Item Description:Online veröffentlicht: 7. Juli 2025
Gesehen am 06.03.2026
Physical Description:Online Resource
ISSN:1098-1004
DOI:10.1155/humu/2475635

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