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.932G>A (p.Gly311Glu)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA350340846

425844 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: fddf9134-3d15-4c50-9816-db009f4768fc

Approved on: 2024-09-10

Published on: 2024-09-10

HGVS expressions

NM_001204.7:c.932G>A

NM_001204.7(BMPR2):c.932G>A (p.Gly311Glu)

NC_000002.12:g.202520166G>A

CM000664.2:g.202520166G>A

NC_000002.11:g.203384889G>A

CM000664.1:g.203384889G>A

NC_000002.10:g.203093134G>A

NG_009363.1:g.148840G>A

ENST00000374580.10:c.932G>A

ENST00000638587.1:c.863G>A

ENST00000374574.2:c.932G>A

ENST00000374580.8:c.932G>A

NM_001204.6:c.932G>A

Uncertain Significance

PM2_Supporting PP3 PM1

PS4 BP4

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

This BMPR2 missense variant c.932G>A is predicted to change a glycine residue to a glutamic acid at position 311. This change occurs in the kinase domain, which is a well established functional domain (PM1 is met). It is absent from gnomAD v2.1.1 controls and gnomAD v4.1 (PM2_supporting is met). There are two ClinVar submissions for this variant, but the affected status of one is "unknown" (PS4 not met). Computational evidence for pathogenicity as evaluated by REVEL generated a score of 0.979 indicating that PP3 is met based on the threshold specified by the PH-VCEP >0.75. In summary, the variant meets the criteria to be classified as variant of uncertain significance (VUS) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1, PM2_Supp, PP3 (VCEP specification version 1.1, 1/18/2024).

PM2_Supporting

Variant absent in gnomAD v2.1.1 controls and gnomAD v4.1.

PP3

REVEL score is 0.979, which meets the PH-VCEP cut-off of >0.75.

PM1

Variant is predicted to change a Glycine residue for a Glutamic Acid in position 311. This change occurs in the kinase domain, which is a well established functional domain.

PS4

Variant is absent from gnomAD v2.1.1 controls (PM2 is met). There are two independent submissions in ClinVar. One of the two PAH patients was included in two publications (PMIDs 19555857 and 26387786). The affected status of the second one is "unknown". Therefore, only one affected individual has been reported.

BP4

REVEL score is 0.979, which is higher than the PH-VCEP cut-off of <0.25.

Curation History

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