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.908G>A (p.Arg303His)

CA2061247

425842 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 059df39a-bbb2-4e25-af5a-965bd14ee707

Approved on: 2024-09-10

Published on: 2024-09-10

HGVS expressions

NM_001204.7:c.908G>A

NM_001204.7(BMPR2):c.908G>A (p.Arg303His)

NC_000002.12:g.202520142G>A

CM000664.2:g.202520142G>A

NC_000002.11:g.203384865G>A

CM000664.1:g.203384865G>A

NC_000002.10:g.203093110G>A

NG_009363.1:g.148816G>A

ENST00000374580.10:c.908G>A

ENST00000638587.1:c.839G>A

ENST00000374574.2:c.908G>A

ENST00000374580.8:c.908G>A

NM_001204.6:c.908G>A

Likely Pathogenic

PS3 PM1

PS4 BA1 PP3 PM2 BS1 BP4

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 BMPR2 c.908G>A variant is a missense variant in exon 7 predicted to result in substitution of arginine to histidine at amino acid position 303 (p. Arg303His). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.00043 (1/2334 alleles) in subpopulation “remaining individuals” which exceeds the ClinGen PH VCEP threshold (<0.01%) for PM2 (PM2 not met). Neither BS1 (≥0.1%) nor BA1 (1%) met. The computational predictor REVEL gives a score of 0.497 indicating neither PP3 (≥0.75) nor BP4 (≤0.25) met. SpliceAI algorithm predicts no deleterious effect on acceptor or donor splice site. The variant is located in the kinase domain (PM1 met). Genetic evidence showed the presence of the variant in only one IPAH patient (PMID:16429395) (PS4 not met). Immunofluorescence staining of Hela cells transfected with an R303H mutant construct showed mislocalization of BMPR2 protein to the endoplasmic reticulum (PMID:25688877) and included positive and negative controls (PS3 met). In summary, the 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: PS3, PM1 (VCEP specification version 1.1, 1/18/2024).

PS3

Immunofluorescence staining of Hela cells transfected with R303H mutant construct showed co-localization of BMPR2 protein with calnexin antibody in endoplasmic reticulum. Quantification of co-localization of BMPR2 R303H mutant with calnexin as compared to wild type was significant (p<= 0.05). Statistically significant co-localization of some other critical BMPR2 cysteine subtitution mutants (C34R, C66R, C118W, D485G, A490D, R491W) was also observed.

Immunofluorescence staining of Hela cells transfected with R303H mutant construct showed colocalization of BMPR2 protein with calnexin antibody which is an endoplasmic reticulum marker. Quantification of co-localization of BMPR2 wild type and R303H mutant with calnexin by pixel analysis showed that co-localization of the mutant is significant. PubMed:25688877

PM1

The variant is present in the kinase domain.

PS4

ClinVar has two entries for pulmonary arterial hypertension - one idiopathic PAH and the other PAH associated with congenital heart disease. The PH VCEP specifications are based on idiopathic and heritable PAH, not associated forms. Thus, PS4 was not met.

BA1

Minor allele frequency in gnomAD v2.1.1 (controls) in subpopulation “remaining individuals” is 0.00043 which is below our threshold of (1%)

PP3

REVEL score for this variant is 0.497 which is below our criteria (>=0.75). Splice AI predicts no impact on splicing.

PM2

Minor allele frequency in gnomAD v2.1.1 (controls) in subpopulation “remaining individuals” is 0.00043 (1/2334 alleles) which is above our threshold of (<0.01%).

BS1

Minor allele frequency in gnomAD v2.1.1 (controls) in subpopulation “remaining individuals” is 0.00043 which is below our threshold of (>=0.1%)

BP4

REVEL score for this variant is 0.497 which is above our criteria for BP4 (<0.25).

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