BMPR2 p.Arg886Cys

The BMPR2 c.2656C>T variant is a missense variant predicted to cause an arginine to cysteine substitution at amino acid position 886. The highest population minor allele frequency in gnomAD v.2.1.1 controls is 0.1130% (11/9738 alleles) in the African/African American population. The population evidence available meets the threshold for BS1 (≥0.1%), but not for BA1 (>5%) or PM2 (<0.01%) as defined by the ClinGen Pulmonary Hypertension VCEP (PH-VCEP). Computational evidence for pathogenicity as evaluated by REVEL generated a score of 0.485 indicating that neither BP4 or PP3 were met since the threshold specified by the PH-VCEP is <0.25 and >0.75, respectively. The amino acid substitution occurs in the c-terminal domain, which is not a well-established functional domain, so PM1 was not met. Criteria not evaluated included PP1, PM6, and PS2 due to the absence of segregation data. BS3 and PS3 were not evaluated due to the lack of functional data for this variant. In summary, the variant meets the criteria to be classified as likely benign (LB) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1 (VCEP specification version 1.1, 1/18/2024).