Variant: NM_001204.7(BMPR2):c.1258T>C (p.Cys420Arg)

CA350341977

425906 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

UUID: aba17240-a290-4993-a1d0-06b357ca31eb

Approved on: 2025-01-22

Published on: 2025-01-22

HGVS expressions

NM_001204.7:c.1258T>C
NM_001204.7(BMPR2):c.1258T>C (p.Cys420Arg)
NC_000002.12:g.202532714T>C
CM000664.2:g.202532714T>C
NC_000002.11:g.203397437T>C
CM000664.1:g.203397437T>C
NC_000002.10:g.203105682T>C
NG_009363.1:g.161388T>C
ENST00000374580.10:c.1258T>C
ENST00000638587.1:c.1189T>C
ENST00000374574.2:c.1258T>C
ENST00000374580.8:c.1258T>C
NM_001204.6:c.1258T>C

Pathogenic

• Met criteria codes: PM2_Supporting PM1_Supporting PP3 PS3 PS4

• Not Met criteria codes: BP4 BS1 BS3 BA1

Expert Panel

Pulmonary Hypertension VCEP

Criteria Specification Information

Criteria Specification: ClinGen Pulmonary Hypertension Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BMPR2 Version 1.1.0

Evidence submitted by expert panel

Pulmonary Hypertension VCEP

BMPR2 c.1258T>C is a missense variant predicted to cause substitution of cysteine to arginine at amino acid position 420 (p.Cys420Arg). This variant resides within the catalytic kinase domain but is not a known critical residue (PM1_moderate met). The variant is absent in gnomAD databases, meeting PM2_supporting criterion (BA1 and BS1 not met). The REVEL score of 0.934 meets PP3_suporting criteria (>=0.75) (BP4 not met). Functional studies indicated subcellular mislocalization of the mutant protein (PMID: 25688877) and decreased receptor-mediated signaling (PMID: 12045205) (PS3 met). At least five unrelated probands have been reported in the literature (PMID: 11115378, 21801371, 27587546, 32634488, 32966279), meeting the PS4 threshold of >4 probands. Alternative missense variants have been reported in the same location but these variants are pending expert panel curation and PM5 is not scored at this time. In summary, this variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS4_strong, PS3_strong, PM1_ moderate, PM2_supporting, PP3 (VCEP specification version 1.1.0, 1/18/2024).

Met criteria codes

• PM2_Supporting: Variant is absent from gnomAD v2.1.1 controls and v4.1.0.
• PM1_Supporting: Variant is present in the catalytic kinase domain but is not a known critical residue.
• PP3: The REVEL score of 0.934 meets the threshold for PP3 (>=0.75) but not BP4 (<=0.25).
• PS3: Fluorescent imaging studies indicate that the expressed protein is mislocalized to the endoplasmic reticulum and cytoplasm, based on overlapping signal with ER markers endoglin and calnexin (PMID: 25688877). Additionally, p.Cys420Arg mutant protein produces a lower response to BMP4 ligand in a luciferase reporter assay (PMID: 12045205). The assays contained both positive and negative controls.
• PS4: At least five unrelated probands have been reported in the literature (PMID: 11115378, 21801371, 27587546, 32634488, 32966279), meeting the threshold of >4 probands.

Not Met criteria codes

• BP4: The REVEL score of 0.934 meets the threshold for PP3 (>=0.75) but not BP4 (<=0.25).
• BS1: Variant is absent from gnomAD v2.1.1 controls and v4.1.0.
• BS3: Fluorescent imaging studies indicate that the expressed protein is mislocalized to the endoplasmic reticulum and cytoplasm, based on overlapping signal with ER markers endoglin and calnexin (PMID: 25688877). Additionally, p.Cys420Arg mutant protein produces a lower response to BMP4 ligand in a luciferase reporter assay (PMID: 12045205). The assays contained both positive and negative controls.
• BA1: Variant is absent from gnomAD v2.1.1 controls and v4.1.0.