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
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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 3
BS3_Supporting BS4 BS1
Not Met criteria codes 7
PM1 PM2 BS2 BP4 PS4 BA1 PP3

Evidence Links 0

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 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
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).
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).
Not Met criteria codes
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.
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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.
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).
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.
Approved on: 2024-05-03
Published on: 2024-05-03
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