Variant: NM_001204.7(BMPR2):c.2618G>A (p.Arg873Gln)

CA2061553

425999 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

UUID: 1b0344d0-aad2-4412-a6e0-ab7c3c719261

HGVS expressions

NM_001204.7:c.2618G>A
NM_001204.7(BMPR2):c.2618G>A (p.Arg873Gln)
NC_000002.12:g.202556283G>A
CM000664.2:g.202556283G>A
NC_000002.11:g.203421006G>A
CM000664.1:g.203421006G>A
NC_000002.10:g.203129251G>A
NG_009363.1:g.184957G>A
ENST00000374580.10:c.2618G>A
ENST00000638587.1:c.2549G>A
ENST00000374574.2:c.1586+3395G>A
ENST00000374580.8:c.2618G>A
NM_001204.6:c.2618G>A

Benign

• Met criteria codes: BS4 BS1 BS3_Supporting

• Not Met criteria codes: PS4 BP4 BA1 PP3 PM2 PM1 BS2

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 c.2618G>A variant (NM_001204.7) in BMPR2 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 873 (p.Arg873Gln). This variant has been reported not to segregate with pulmonary arterial hypertension in one affected family member from one family (BS4; Internal lab contributor). The highest population minor allele frequency in gnomAD v2.2.1 controls is 0.001595 in Other East Asian population, which is higher than the ClinGen Pulmonary Hypertension VCEP threshold (≥0.001) for BS1, and therefore meets this criterion (BS1). In vitro reporter system assay in mouse embryonic endothelial cells showed that the c.2618 G>A variant activate BRE-Luc (specific reporter gene for Smad1/5 activation) in response to BMP4 treatment in a similar way as the wild-type BMPR2 reporter gene. However the impairment of another function through an alternative signaling pathway of BMPRII could not be excluded (PMID 25429696)(BS3_Supporting). In summary, this variant meets the criteria to be classified as benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP (specification version 1.1, 1/18/2024): BS4, BS1, BS3_Supporting.

Met criteria codes

• BS4: This variant has been reported not to segregate with pulmonary arterial hypertension in one affected family member from one family (BS4; Internal lab contributors).
• BS1: The highest population minor allele frequency in gnomAD v2.2.1 is 0.001595 in Other East Asian population, which is higher than the ClinGen Pulmonary Hypertension VCEP threshold (≥0.001) for BS1, and therefore meets this criterion (BS1).
• BS3_Supporting: In vitro reporter system assay in mouse embryonic endothelial cells showed that the c.2618 G>A variant activate BRE-Luc (specific reporter gene for Smad1/5 activation) in response to BMP4 treatment in a similar way as the wild-type BMPR2 reporter gene. However the impairment of another function through an alternative signaling pathway of BMPRII could not be excluded (PMID 25429696)(BS3_Supporting).

Not Met criteria codes

• PS4: This variant has been reported in one proband meeting pulmonary arterial hypertension (SCV000576302.1). However, PS4 cannot be applied because gnomAD v2.1.1 frequency is >0.01% (PM2_Supporting Not Met).
• BP4: The computational predictor REVEL gives a score] of 0.551, which is neither above nor below the thresholds predicting a damaging or benign impact on BMPR2 function.
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: The computational predictor REVEL gives a score] of 0.551, which is neither above nor below the thresholds predicting a damaging or benign impact on BMPR2 function.
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: This variant does not reside within a region of BMPR2 that is defined as a mutational hotspot or critical functional domain by the ClinGen Pulmonary Hypertension VCEP.
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2024-05-03

Published on: 2024-05-03