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]

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

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: 2024-05-03

Published on: 2024-05-03

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

Likely Benign

BS3

BS1 BP4 PS1 PP3 PM5 PM1 PM2

Evidence Links 5

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.1509A>C variant is a missense variant predicted to cause substitution of glutamate by aspartate at amino acid 503 (p.Glu503Asp). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.0001105 (1/9046 alleles) in East Asian population, which is higher than the ClinGen PH VCEP threshold (<0.01%) for PM2 but lower than the threshold (>0.1%) for BS1. Therefore, this variant does not meet either of these population criteria. The computational predictor REVEL gives a score of 0.662, which is neither above nor below the thresholds predicting a damaging or benign impact on BMPR2 function. Luciferase assay data indicated that variant transcriptional activity was comparable to wild-type, indicating no deleterious effect (BS3; PMID: 18321866). The p.Glu503Asp (p.E503D) mutant also shows normal localization to the plasma membrane (PMID: 25688877) and no effect on cell viability (PMID: 30809644). In summary, this variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS3. (VCEP specifications version 1.1, 1/18/2024)

BS3

Cells transfected with the p.G503D variant have no damaging effects on cellular localisation (PMID: 25688877), transcriptional activity (PMID: 18321866) or cell viability (PMID: 30809644)

Transcriptional activity of the p.G182D variant is comparable to wild-type using a luciferase assay PubMed:18321866

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

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

REVEL score is 0.662 so does not meet the threshold to be classified as deleterious (REVEL >0.75)

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. 1. Greenwald et al 1999. (Nat Struct Biol 6:18–22. PMID: 9886286) 2. Machado et al. 2006 (Hum Mutat. 2006 ;27(2):121-32. PMID: 16429395)

Critical domain PubMed:9886286

critical domain PubMed:16429395

PM2

Allele frequency in the East Asian population (gnomAD v2.1.1 controls) is greater than 0.01% (MAF: 1/9046 = 0.00011)

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