Variant: NM_001204.7(BMPR2):c.125A>G (p.Gln42Arg)

CA350399166

425706 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

UUID: 65f85c52-3e03-404a-af70-e2e0681ffa25

Approved on: 2025-01-22

Published on: 2025-01-22

HGVS expressions

NM_001204.7:c.125A>G
NM_001204.7(BMPR2):c.125A>G (p.Gln42Arg)
NC_000002.12:g.202464857A>G
CM000664.2:g.202464857A>G
NC_000002.11:g.203329580A>G
CM000664.1:g.203329580A>G
NC_000002.10:g.203037825A>G
NG_009363.1:g.93531A>G
ENST00000374580.10:c.125A>G
ENST00000638587.1:c.50A>G
ENST00000374574.2:c.125A>G
ENST00000374580.8:c.125A>G
ENST00000479069.1:n.32A>G
NM_001204.6:c.125A>G

Uncertain Significance

• Met criteria codes: PM2_Supporting PP3 PM1

• Not Met criteria codes: BA1 BP4 BS1 PM5 PS1 PS4

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

The NM_001204.7(BMPR2):c.140G>A (p.Gly47Asp) variant is a missense variant located within exon 2 of BMPR2, predicted to cause substitution of glycine to an aspartic acid. This variant is located within the conserved extracellular domain of the protein but does not affect a known critical residue (PM1_moderate met). The variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting met). The REVEL prediction algorithm score is 0.78, which is above the threshold of 0.75 for pathogenicity (PP3_supporting met). The variant has been reported in an individual with PAH associated with congenital heart disease (PMID: 15358693) but not in patients with hereditary or idiopathic PAH (PS4 not met). Alternative alleles at the same nucleotide or amino acid have not been reported (PS1 and PM5 not met). Functional studies have not been reported (PS3 not assessed). Neither segregation or maternity/paternity data are available (PS2, PP1, BS4 not evaluated). In summary, this variant meets the criteria to be classified as a variant of unknown significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM2_supporting, PP3_supporting (VCEP specification version 1.1.0, 1/18/2024).

Met criteria codes

• PM2_Supporting: Absent from gnomAD v2.1.1 (controls) and v4.1.
• PP3: REVEL prediction algorithm score is 0.78, which is above the threshold of 0.75 for pathogenicity.
• PM1: Located within the conserved extracellular domain of the protein but does not affect a known critical residue.

Not Met criteria codes

• BA1: Absent from gnomAD v2.1.1 (controls) and v4.1.
• BP4: REVEL prediction algorithm score is 0.78, which is above the threshold of 0.75 for pathogenicity.
• BS1: Absent from gnomAD v2.1.1 (controls) and v4.1.
• PM5: Alternative alleles at the same nucleotide have not been reported.
• PS1: Alternative alleles at the same amino acid have not been reported.
• PS4: The variant has been reported in an individual with PAH associated with congenital heart disease (PMID: 15358693) but not in patients with hereditary or idiopathic PAH.