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

CA278089

8806 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

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

Pathogenic

• Met criteria codes: PS2 PS4 PS3_Supporting PP3 PP1 PM1_Strong PM5 PM2_Supporting

• Not Met criteria codes: PS1 BA1 PP2 PM4 BS1 BS3 BP7 BP3 BP4 BP1

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

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

• 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).
• 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.
• 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.
• 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.
• 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

• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: 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
• 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