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.100T>C (p.Cys34Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA350399040

425702 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: e18b79b3-7e9c-473b-a771-5f33b02792cf

Approved on: 2024-09-20

Published on: 2024-09-20

HGVS expressions

NM_001204.7:c.100T>C

NM_001204.7(BMPR2):c.100T>C (p.Cys34Arg)

NC_000002.12:g.202464832T>C

CM000664.2:g.202464832T>C

NC_000002.11:g.203329555T>C

CM000664.1:g.203329555T>C

NC_000002.10:g.203037800T>C

NG_009363.1:g.93506T>C

ENST00000374580.10:c.100T>C

ENST00000638587.1:c.25T>C

ENST00000374574.2:c.100T>C

ENST00000374580.8:c.100T>C

ENST00000479069.1:n.7T>C

NM_001204.6:c.100T>C

Pathogenic

PS3 PP3 PM2_Supporting PS4_Supporting PM1_Strong PM5_Supporting

PS1

Evidence Links 2

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.100T>C variant is a missense variant predicted to cause a cysteine to arginine substitution at amino acid position 34 (p.Cys34Arg). The variant is absent from gnomAD v.2.1.1 and v4.1 (PM2_supporting) and has been reported in two unrelated PAH probands (PMID: 29650961) (PS4_supporting). The variant is located within the extracellular ligand-binding domain and p.Cys34 is a critical residue for protein function (PM1_strong). Two additional likely pathogenic variants, c.101G>T (p.Cys34Phe) and c.102T>G (p.Cys34Trp) have been reported at the same residue (PMID: 27453251, PMID: 30578397) (PM5_supporting). HeLa cells transfected with a BMPR2 p.C34R construct demonstrated that the mutant protein is mislocalized in the cell and does not reach the plasma membrane, with some retention in the ER/Golgi (PMID: 25688877) (PS3). In silico prediction (REVEL = 0.939) is consistent with a pathogenic effect for this variant (PP3). In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS3, PS4_supporting, PM1_strong, PM2_supporting, PM5_supporting, PP3 (VCEP specification version v 1.1, 1/18/2024).

PS3

Cells transfected with the p.C34R variant show a damaging effect on cellular localisation with some ER/Golgi retention (John et al. 2015)

The p.C34R mutant does not localise to the plasma membrane PubMed:25688877

PP3

REVEL score is 0.939 so meets the threshold to be classified as deleterious (REVEL >0.75)

PM2_Supporting

Variant allele is absent from gnomAD v2.1.1 and v4.1

PS4_Supporting

Variant has been reported in two unrelated IPAH patients (Graf et al. 2018, PMID: 29650961). PM2 is met

PM1_Strong

Variant is located in the extracellular ligand-binding domain and the mutated residue is critical for correct protein folding, as determined by multiple sequence alignment and X-crystallography studies

p.Cys34 is a highly conserved residue in the ligand-binding domain PubMed:9886286

PM5_Supporting

Two missense variants classified as likely pathogenic have been reported at the same amino acid residue

PS1

Same amino acid change has not been reported previously

Curation History

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