ClinVar

Description

The c.2618G>A variant (NM_001204.7) in BMPR2 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 873 (p.Arg873Gln). This variant has been reported not to segregate with pulmonary arterial hypertension in one affected family member from one family (BS4; Internal lab contributor). The highest population minor allele frequency in gnomAD v2.2.1 controls is 0.001595 in Other East Asian population, which is higher than the ClinGen Pulmonary Hypertension VCEP threshold (>=0.001) for BS1, and therefore meets this criterion (BS1). In vitro reporter system assay in mouse embryonic endothelial cells showed that the c.2618 G>A variant activate BRE-Luc (specific reporter gene for Smad1/5 activation) in response to BMP4 treatment in a similar way as the wild-type BMPR2 reporter gene. However the impairment of another function through an alternative signaling pathway of BMPRII could not be excluded (PMID 25429696)(BS3_Supporting). In summary, this variant meets the criteria to be classified as benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP (specification version 1.1, 1/18/2024): BS4, BS1, BS3_Supporting.