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]

Link to SEPIO compliant JSON-LD document

Variant: NM_001204.7(BMPR2):c.968-3C>G

CA645293968

425852 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: f792e131-225a-409f-af59-2939d0c0e1d2

HGVS expressions

NM_001204.7:c.968-3C>G

NM_001204.7(BMPR2):c.968-3C>G

NC_000002.12:g.202530791C>G

CM000664.2:g.202530791C>G

NC_000002.11:g.203395514C>G

CM000664.1:g.203395514C>G

NC_000002.10:g.203103759C>G

NG_009363.1:g.159465C>G

ENST00000374580.10:c.968-3C>G

ENST00000638587.1:c.899-3C>G

ENST00000374574.2:c.968-3C>G

ENST00000374580.8:c.968-3C>G

NM_001204.6:c.968-3C>G

Uncertain Significance

PM2_Supporting PP3 PS4_Supporting

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 BMPR2 c.968-3C>G is an intronic variant in intron 7. This variant is absent from both gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The variant has been reported in 2 unrelated PAH patients (PMID: 26387786 and GeneDx submission to ClinVar) (PS4_Supporting). PVS1 is not applied because it is a non-canonical splice site variant without mRNA processing data. The computational splicing predictor SpliceAI gives a score of 0.98 for acceptor loss, predicting that the variant disrupts the acceptor splice site of intron 7 (PP3). In summary, the variant is classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting, PS4_supporting, PP3 (VCEP specification version 1.1, 1/18/2024).

PM2_Supporting

The variant is absent from both gnomAD v2.1.1 and v3.1.2.

PP3

The computational splicing predictor SpliceAI gives a score of 0.98 for acceptor loss, predicting that the variant disrupts the acceptor splice site of intron 7 of BMPR2.

PS4_Supporting

The variant has been reported in 2 unrelated PAH patients: first proband is associated with the publication (PMID: 26387786) and the second proband, with no further information for co-segregation, is from an internal lab contributor GeneDx (PS4_Supporting).

Approved on: 2024-05-03

Published on: 2024-05-03

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