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]
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  • 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.1042G>A (p.Val348Ile)

CA2061283

333642 (ClinVar)

Gene: BMPR2
Condition: pulmonary arterial hypertension
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 82599d46-7d29-49db-b201-a5da48a2deb3
Approved on: 2024-05-03
Published on: 2024-05-03

HGVS expressions

NM_001204.7:c.1042G>A
NM_001204.7(BMPR2):c.1042G>A (p.Val348Ile)
NC_000002.12:g.202530868G>A
CM000664.2:g.202530868G>A
NC_000002.11:g.203395591G>A
CM000664.1:g.203395591G>A
NC_000002.10:g.203103836G>A
NG_009363.1:g.159542G>A
ENST00000374580.10:c.1042G>A
ENST00000638587.1:c.973G>A
ENST00000374574.2:c.1042G>A
ENST00000374580.8:c.1042G>A
NM_001204.6:c.1042G>A

Likely Benign

Met criteria codes 2
BS1 PS3_Supporting
Not Met criteria codes 10
BP4 BP1 PS1 PS4 BA1 PP3 PP2 PM1 PM5 PM2

Evidence Links 1

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.1042G>A variant is a missense variant predicted to cause a valine to isoleucine substitution at amino acid 348 (p.Val348Ile). The highest population minor allele frequency in gnomAD v2.1.1 controls is 0.88% (62/7044) alleles in the “Other” East Asian population, which is higher than the ClinGen Pulmonary Hypertension VCEP threshold >0.1% for BS1, and therefore meets this criterion (BS1). PP3 was not met. The computational predictor REVEL gives a score of 0.744 which is below the threshold of >0.75 for pathogenicity. Densitometry analysis indicated a modest reduction in p-SMAD levels but this was not consolidated by additional experimental analysis (PS3_supporting). In summary the variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1, PS3_supporting (VCEP specification version 1.1, 1/18/2024).
Met criteria codes
BS1
East Asian "Other" control population frequency: 0.88% (62/7044) --> >0.1% cut-off for BS1 for PAH
PS3_Supporting
Densitometry analysis showed a modest reduction of p-SMAD expression (PMID: 36675162) but this was not confirmed by an independent assay, therefore PS3 is downgraded to supporting.
Functional assessment by densitometry analysis demonstrates p-SMAD levels are moderately diminished in cells transfected with p.V348I, in relation to nonsyndromic oligodontia PubMed:36675162
Not Met criteria codes
BP4
REVEL score =0.744 --> not ≤0.75
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
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No gnomAD control population frequency with at least 1000 individuals >1%
PP3
REVEL score 0.744 --> not ≥0.75 as cut-off for BMPR2 variants in PAH
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Variant is located in the kinase domain but the mutated residue is not a critical amino acid as determined by evolutionary conservation and structural analysis
PM5
no missense at same amino acid reported as (likely) pathogenic
PM2
Variant present in the control population of gnomAD v2.1.1 at a frequency higher than the 0.01% cut-off for PM2 for PAH.
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