Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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

CA16610662

409829 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

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

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

PVS1 PM2_Supporting PP3 PS4_Supporting

BS1 BA1

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

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 It is predicted to create a strong acceptor site gain (PP3_supporting) and PH VCEP internal unpublished RNA sequencing data confirmed an effect on splicing leading to NMD.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)

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PH VCEP internal unpublished RNA sequencing data confirmed an effect on splicing leading to NMD.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)

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).

BS1

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

BA1

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

Approved on: 2024-05-03

Published on: 2024-05-03

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