Variant: NM_001204.7(BMPR2):c.968-5A>G

CA16610662

409829 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

UUID: cc7890de-9825-43e3-9d6e-06fe2b6a8c9d

Approved on: 2024-05-03

Published on: 2024-05-03

HGVS expressions

NM_001204.7:c.968-5A>G
NM_001204.7(BMPR2):c.968-5A>G
NC_000002.12:g.202530789A>G
CM000664.2:g.202530789A>G
NC_000002.11:g.203395512A>G
CM000664.1:g.203395512A>G
NC_000002.10:g.203103757A>G
NG_009363.1:g.159463A>G
ENST00000374580.10:c.968-5A>G
ENST00000638587.1:c.899-5A>G
ENST00000374574.2:c.968-5A>G
ENST00000374580.8:c.968-5A>G
NM_001204.6:c.968-5A>G

Pathogenic

• Met criteria codes: PP3 PS4_Supporting PVS1 PM2_Supporting

• 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 NM_001204.7(BMPR2) c.968-5A>G is an intronic variant at Intron 7. This variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting). It is predicted to create a strong acceptor site gain (PP3_supporting) and PH VCEP internal unpublished RNA sequencing data confirmed an effect on splicing leading to NMD. The c.968-5G>A variant leads to the inclusion of 4 bases of intron 7 into the mature mRNA creating a frameshift and a STOP codon at position 327(PVS1_strong). The variant has been reported in 2 unrelated PAH patients: first proband is associated with the publication (PMID: 19555857) and the second proband, with no further information for co-segregation, is from an internal lab contributor (PS4_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1_strong, PM2_supporting, PS4_supporting and PP3_supporting (VCEP specifications version 1.1, 1/18/2024)

Met criteria codes

• PP3: This variant alters the canonical splice donor site of intron 7. Splice AI predicts a strong acceptor gain (score: 0.99).
• PS4_Supporting: The variant has been reported in 3 unrelated PAH patients (1 proband from PMID: 19555857, a ClinVar entry by a clinical laboratory, and 1 from a PH VCEP internal contributor).
• PVS1: PH VCEP internal unpublished RNA sequencing data confirmed an effect on splicing leading to NMD. The c.968-5G>A variant leads to the inclusion of 4 bases of intron 7 into the mature mRNA creating a frameshift and a STOP codon at position 327
• PM2_Supporting: This variant is absent from gnomAD controls (v2.1.1 and v3.1.2)

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline