Variant: NM_001204.7(BMPR2):c.1277-9A>G

CA645293838

425917 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

UUID: bd24bcd2-c2d0-4803-b776-28a371963ce6

Approved on: 2025-05-05

Published on: 2025-05-05

HGVS expressions

NM_001204.7:c.1277-9A>G
NM_001204.7(BMPR2):c.1277-9A>G
NC_000002.12:g.202542302A>G
CM000664.2:g.202542302A>G
NC_000002.11:g.203407025A>G
CM000664.1:g.203407025A>G
NC_000002.10:g.203115270A>G
NG_009363.1:g.170976A>G
ENST00000374580.10:c.1277-9A>G
ENST00000638587.1:c.1208-9A>G
ENST00000374574.2:c.1277-9A>G
ENST00000374580.8:c.1277-9A>G
NM_001204.6:c.1277-9A>G

Pathogenic

• Met criteria codes: PM2_Supporting PS4_Moderate PVS1

• Not Met criteria codes: BA1 BS1

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 BMPR2 c.1277-9A>G variant is a non-canonical splice site (-9) variant located in intron 9. The variant is absent from gnomAD v.2.1.1 and v4.1.0 (PM2_supporting) and was reported in four cases (PMID: 18356561, 20534176, 27613157) (PS4_moderate). In silico prediction (SpliceAI) indicates likely loss of the acceptor splice site (score = 0.97). cDNA analysis demonstrates an aberrant splice product leading to premature truncation (p.Gly426Aspfs*47) and, thus, likely nonsense mediated decay (PMID: 18356561 and private communication: Soubrier) (PVS1 (RNA)). No familial segregation data were available. In summary, the 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: PVS1 (RNA), PM2_supporting, PS4_moderate (VCEP specification version v1.1, 1/18/2024).

Met criteria codes

• PM2_Supporting: Variant is absent from controls (gnomAD v2.1.1 and v4.1.0)
• PS4_Moderate: Variant is observed in four ostensibly unrelated individuals with PAH
• PVS1: cDNA sequence analysis shows that the variant has an effect on splicing, which has been confirmed via private communication (Prof. Florent Soubrier) as resulting in premature truncation of the translated protein (p.Gly426Aspfs*47)

Not Met criteria codes

• BA1: Variant is not present in gnomAD v2.1.1 and v4.1.0
• BS1: Variant is not present in gnomAD v2.1.1 and v4.1.0