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.1157A>G (p.Glu386Gly)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA350341740

425886 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 865776fa-1443-4399-8d06-8a977a1fa2ba

Approved on: 2024-11-06

Published on: 2024-11-06

HGVS expressions

NM_001204.7:c.1157A>G

NM_001204.7(BMPR2):c.1157A>G (p.Glu386Gly)

NC_000002.12:g.202532613A>G

CM000664.2:g.202532613A>G

NC_000002.11:g.203397336A>G

CM000664.1:g.203397336A>G

NC_000002.10:g.203105581A>G

NG_009363.1:g.161287A>G

ENST00000374580.10:c.1157A>G

ENST00000638587.1:c.1088A>G

ENST00000374574.2:c.1157A>G

ENST00000374580.8:c.1157A>G

NM_001204.6:c.1157A>G

Likely Pathogenic

PM2_Supporting PP3 PM5_Supporting PM1_Strong

BP4 PS1

Evidence Links 1

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.1157A>G (p.Glu386Gly) variant is harboured in exon 9 of the BMPR2 gene, encoding the functionally relevant catalytic kinase domain and impacts an amino acid indispensable to kinase structure and function (PM1_strong). The variant has been reported once in an IPAH subject (PMID: 21801371). The variant is absent from gnomAD v2.1.1 (controls) and v4.1.0 (PM2_supporting). The REVEL prediction algorithm score is 0.993, AlphaMissense is 0.9902 indicating pathogenicity (PP3_met). PS2 was not assessed due to lack of paternity data. Functional studies have not been conducted for this variant (PS3 not assessed). Four additional likely pathogenic variants (p.Glu386Ala, p.Glu386Gln, p.Glu386Lys, p.Glu386Val) have been reported at the same position (PMID: 26387786) (PM5_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_strong, PM2_supporting, PP3, PM5_supporting (VCEP specification version 1.1.0, 1/18/2024).

PM2_Supporting

Variant is absent in gnomAD v2.1.1 (controls) and v4.1.0 populations

PP3

REVEL score is 0.993, which meets the threshold for pathogenicity (>0.75). AlphaMissense score is 0.990, indicating likely pathogenicity.

PM5_Supporting

Four additional missense changes affecting the same residue have been reported: p.Glu386Ala, p.Glu386Lys, p.Glu386Gln, p.Glu386Val. All are classified as likely pathogenic, based on the ACMG/AMP criteria applied as specified by the ClinGen pulmonary hypertension VCEP.

PM1_Strong

The p.Glu386 residue is located in the functionally relevant catalytic kinase domain and impacts an amino acid indispensable to kinase structure and function (Agnew et al. 2021).

p.Glu386 is indispensable to kinase structure and function. PubMed:34400635

BP4

REVEL score is 0.993, which does not meet the threshold for benignity (<0.25).

PS1

Same amino acid change has not been previously reported.

Curation History

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