Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_001204.7(BMPR2):c.1472G>A (p.Arg491Gln)

CA278089

8806 (ClinVar)

Gene: BMPR2
Condition: pulmonary arterial hypertension
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 2649bacd-6839-4dbf-bad0-fa4462173e43
Approved on: 2024-05-03
Published on: 2024-05-03

HGVS expressions

NM_001204.7:c.1472G>A
NM_001204.7(BMPR2):c.1472G>A (p.Arg491Gln)
NC_000002.12:g.202552774G>A
CM000664.2:g.202552774G>A
NC_000002.11:g.203417497G>A
CM000664.1:g.203417497G>A
NC_000002.10:g.203125742G>A
NG_009363.1:g.181448G>A
ENST00000374580.10:c.1472G>A
ENST00000638587.1:c.1403G>A
ENST00000374574.2:c.1472G>A
ENST00000374580.8:c.1472G>A
NM_001204.6:c.1472G>A
More

Pathogenic

Met criteria codes 8
PM1_Strong PS3_Supporting PS2 PS4 PP3 PP1 PM5 PM2_Supporting
Not Met criteria codes 10
BA1 BS1 BS3 BP7 BP3 BP4 BP1 PS1 PP2 PM4

Evidence Links 2

Expert Panel

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.1472G>A (p.Arg491Gln) variant is a missense variant predicted to cause an arginine to glutamine substitution at amino acid position 491. The variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting). The variant co-segregated with PAH in a large Iberian family with at least four confirmed meioses (PP1; PMID: 30894412), is recurrent in more than four unrelated PAH patients (PS4; PMID: 20534176 and PMID: 29023671) and confirmed de novo in at least two probands with unaffected parents (PS2; PMID: 10903931 and PMID: 23298310). c.1472G>A resides in the conserved kinase domain of BMPR-II and changes an invariant and critical arginine residue at position 491 (PM1_Strong; PMID: 7768349, PMID: 34400635), likely impairing interaction with other BMP receptors. The functional assay evidence for a role in BMP receptor interactions was based on a PH VCEP approved luciferase activity assay but lacked known pathogenic and benign variant controls, so PS3 was scored at the supporting level (PS3_supporting; PMID: 18321866). A different amino acid change at the same position (p.Arg491Trp) was classified as pathogenic (PM5). PP3 was met based on a REVEL score of 0.962. In summary, this variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS2, PS3_supporting, PS4, PM1_strong, PM2_supporting, PM5, PP1, PP3 (VCEP specification version v 1.1, 1/18/2024).
Met criteria codes
PM1_Strong
Mutation R491Q is a critical residue located within the Kinase Domain of the protein. Arginine in position 491 of the BMPRII protein is indispensable for signaling.
Destabilization free energies were calculated using the Eris server. The R491Q mutation was studied using predictive tools. They show this mutation is highly destabilizing . PubMed:31797984
Mutations of the residues within the αH-αI linker in the BMPR2 kinase domain can disrupt ALK2/BMPR2 kinase dimerization and downstream signaling. PubMed:34400635
PS3_Supporting
Two studies were identified that provide evidence that suggest a damaging effect caused by the 1472G>A mutation on receptor activity. PS3_supporting is applied because the studies did not use know pathogenic or benign variants as validation controls.
PS2
Confirmed de novo in at least two probands with unaffected parents.
PS4
More than 4 probands with the 1472G>A mutation and PAH were reported in the literature. The variant was not observed in the control population from gnomAD. Prevalence of variant in affected individuals (>4) is higher compared to controls (0).
PP3
The arginine residue in position 491 is highly conserved across species. REVEL score was used as a predictive tool for deleteriousness. REVEL score = 0.962
PP1
The variant co-segregated with PAH in a large Iberian family with at least four confirmed meioses.
PM5
c.1471C>T (p. Arg491Trp) is pathogenic
PM2_Supporting
The variant is absent from gnomAD v3.1.2 genomes and gnomAD v2.1.1 genomes and exomes.
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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