Adaptation of ACMG/AMP guidelines for clinical classification of variants in Pulmonary Arterial Hypertension resolves variants of unclear pathogenicity in ClinVar.

PURPOSE

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 ( ) gene. We formed a ClinGen variant curation expert panel to devise guidelines for the clinical interpretation of variants identified in PAH patients.

METHODS

The general ACMG/AMP variant classification criteria were refined for PAH and adapted to following ClinGen procedures. Subsequently, these specifications were tested independently by three members of the curation expert panel on 28 representative variants selected from ClinVar, and then presented and discussed in the plenum.

RESULTS

Application of the final variant specifications resolved 6 of 9 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 reclassifications based on the presence or absence of supporting mRNA splicing data.

CONCLUSION

The variant specifications provide an international framework and a useful tool for variant classification and can be applied to increase confidence and consistency in interpretation for diagnostic laboratories, clinical providers, and patients.