ClinVar

Description

The NM_001204.7(BMPR2) c.1040A>C variant is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 347 (p.Cys347Tyr). This variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting). The computational predictor REVEL gives a score of 0.939, which is above the thresholds predicting a damaging impact on BMPR2 function (PP3). A different change affecting the same amino acid (c.1039T>C p.(Cys347Arg); PMID: 26387786) has been reported as likely pathogenic (PM5_supporting). Cytoplasmatic retention assay demonstrates impaired signaling with subcellular localization in HeLa cells showing retainment in endoplasmatic reticulum, not significantly different to empty plasmid. However, this analysis lacks validation controls (PMID: 12045205; PS3_supporting). This variant has been reported in 5 probands meeting pulmonary arterial hypertension criteria (PS4 ; PMIDs 10973254; 26645265; 29631995; 31727138). In summary, this variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting, PS4, PP3, PM5_supporting, PS3_supporting (VCEP specifications version 1.1, 1/18/2024).