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]

Variant: NM_001204.7(BMPR2):c.247+1_247+7del

Curation Version - 2.1
Curation History
JSON LD for Version 2.1

CA645294001

425731 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: fd2208b7-4519-414d-a9a6-9e86d8c2f289

Approved on: 2025-10-07

Published on: 2025-10-07

HGVS expressions

NM_001204.7:c.247+1_247+7del

NM_001204.7(BMPR2):c.247+1_247+7del

NC_000002.12:g.202464980_202464986del

CM000664.2:g.202464980_202464986del

NC_000002.11:g.203329703_203329709del

CM000664.1:g.203329703_203329709del

NC_000002.10:g.203037948_203037954del

NG_009363.1:g.93654_93660del

ENST00000374580.10:c.247+1_247+7del

ENST00000638587.1:c.173_176+3del

ENST00000374574.2:c.247+1_247+7del

ENST00000374580.8:c.247+1_247+7del

ENST00000479069.1:n.154+1_154+7del

NM_001204.6:c.247+1_247+7del

Likely Pathogenic

PVS1_Strong PM2_Supporting PS1_Moderate

BS1 BP3 PP3 BA1 PM4

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.247+1_247+7del variant is a 7 bp deletion spanning the canonical donor splice site of intron 2. This variant is absent from gnomAD v2.1.1 controls and v4.1 (PM2_supporting). It is predicted to cause skipping of biologically relevant exon 2 (171 bp), resulting in an in-frame deletion of amino acids Ala26-Gln82 within the ligand-binding domain, but is predicted to escape nonsense-mediated decay (PVS1_strong). The predictions were recorded under PVS1 so PP3 was not applied to avoid double counting. Another variant affecting this splice site, c.247+6, has been shown by RT-PCR to produce incomplete transcripts (Cogan et. al 2006 PMID:16728714) and was classified as likely pathogenic by the PH VCEP (PS1_moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1_strong, PS1_moderate, PM2_supporting. (VCEP specifications version 1.1, 1/18/2024)

PVS1_Strong

This deletion spans the canonical splice donor site of intron 2 (+1 to +7). Splice AI predicts loss of donor splice site (score: 0.95) that may lead to skipping of biologically relevant exon 2 (171bp), resulting in an in-frame deletion of 57 amino acids (26-82) within the extracellular ligand-binding domain. However, there is not any reported functional evidence to escalate this criterion.

PM2_Supporting

This variant is absent from gnomAD controls (v2.1.1 and v3.1.2) and not reported in other databases including ExAC, 1000 Genomes, ESP, PAGE (October 9, 2022)

PS1_Moderate

Another variant affecting this splice site, c.247+6, was shown by RT-PCR to produce incomplete transcripts (Cogan et. al 2006 PMID:16728714), and were classified as likely pathogenic by the PH VCEP.

BS1

Variant not present in control populations

BP3

PP3

Variant is a 7 bp deletion spanning the donor splice site of intron 2. Splice AI predicts loss of donor splice site (score: 0.95). MaxEntScan score is 3.24 for WT BMPR2 and 0.21 for variant deletion. Lastly, varSEAK classified this variant as Class 5, or highly affecting splicing. However, the predictions were recorded under PVS1 so PP3 was not applied to avoid double counting.

BA1

Variant not present in control populations

PM4

Splicing predictions (SpliceAI, MaxEntScan, NNSplice and varSEAK) indicate loss of donor splice site and/or possible use of nearby cryptic splice sites leading to protein length changes. However, no functional data are available to support these predictions and the variant has been scored under PVS1.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.