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.1509A>C (p.Glu503Asp)

Curation Version - 2.1
Curation History
JSON LD for Version 2.1

CA16610570

409828 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 43fb2d44-b756-4904-9ef4-19f0070db7a5

Approved on: 2026-01-30

Published on: 2026-01-30

HGVS expressions

NM_001204.7:c.1509A>C

NM_001204.7(BMPR2):c.1509A>C (p.Glu503Asp)

NC_000002.12:g.202552811A>C

CM000664.2:g.202552811A>C

NC_000002.11:g.203417534A>C

CM000664.1:g.203417534A>C

NC_000002.10:g.203125779A>C

NG_009363.1:g.181485A>C

ENST00000374580.10:c.1509A>C

ENST00000638587.1:c.1440A>C

ENST00000374574.2:c.1509A>C

ENST00000374580.8:c.1509A>C

NM_001204.6:c.1509A>C

Uncertain Significance

PM2

BS3 BS1 BP4 PS1 PP3 PM5 PM1

Evidence Links 4

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 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Pulmonary Hypertension VCEP

The NM_001204.7(BMPR2) c.1509A>C variant is a missense variant predicted to cause substitution of glutamate by aspartate at amino acid 503 (p.Glu503Asp). The maximum subpopulation allele frequency in gnomAD v4.1 is 8.474e-7 (1/1180024 alleles, non-Finnish Europeans), below the PH VCEP threshold of 0.01% (PM2 met). The variant REVEL score (0.662) meets the PH VCEP threshold of >=0.644 but the AlphaMissense score (0.2603) and CADD score (17.69) are below the thresholds for pathogenicity (PP3 not met). The variant does not affect protein localization to the plasma membrane (PMID: 25688877) or cell viability (PMID: 30809644). A single luciferase assay demonstrated comparable canonical transcriptional activity to wild-type (PMID: 18321866). However, the lack of effect on canonical signaling in one assay without replication in an independent assay, did not provide conclusive evidence for non-criticality (BS3 not met). In summary, this variant meets the criteria to be 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. (VCEP specifications version 2.0, 1/30/2026)

PM2

The maximum subpopulation allele frequency in gnomAD v4.1 is 8.474e-7 (1/1180024 alleles, non-Finnish Europeans), below the PH VCEP threshold of 0.01%.

BS3

Cells transfected with the p.E503D variant have no damaging effects on cellular localization (PMID: 25688877), transcriptional activity (PMID: 18321866), or cell viability (PMID: 30809644). However, the lack of effect on canonical signaling in one assay without replication in an independent assay, does not provide conclusive evidence for non-criticality.

The p.E503D mutant shows normal localisation to the plasma membrane PubMed:25688877

Cells transfected with the p.E503D variant show no detrimental effect on cell viability PubMed:30809644

Transcriptional activity of the p.E503D variant is comparable to wild-type using a luciferase assay PubMed:18321866

BS1

Allele frequency is less than 0.1% in gnomAD v2.1.1 controls

BP4

REVEL score is 0.662 so does not meet the threshold to be classified as no impact on gene or gene product (REVEL <0.25).

PS1

Amino acid change has not been reported previously

PP3

The variant REVEL score (0.662) meets the PH VCEP threshold of >=0.644 but the AlphaMissense score (0.2603) and CADD score (17.69) are below the thresholds for pathogenicity.

PM5

Amino acid residue has not been previously reported as mutated

PM1

Variant is located in the kinase domain but the mutated residue is not a critical amino acid as determined by evolutionary conservation and structural analysis (Hanks and Hunter, 1995; PMID: 7768349).

p.E503 is a poorly conserved residue across the eukaryotic protein kinase superfamily PubMed:7768349

Curation History

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