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 computed assertion could be determined for this classification!


Variant: NM_001204.7(BMPR2):c.1228G>A (p.Gly410Arg)

CA350341903

425897 (ClinVar)

Gene: BMPR2
Condition: pulmonary arterial hypertension
Inheritance Mode: Autosomal dominant inheritance
UUID: e5d3e045-656c-4239-a83d-a231e97ff06d
Approved on: 2025-01-03
Published on: 2025-01-03

HGVS expressions

NM_001204.7:c.1228G>A
NM_001204.7(BMPR2):c.1228G>A (p.Gly410Arg)
NC_000002.12:g.202532684G>A
CM000664.2:g.202532684G>A
NC_000002.11:g.203397407G>A
CM000664.1:g.203397407G>A
NC_000002.10:g.203105652G>A
NG_009363.1:g.161358G>A
ENST00000374580.10:c.1228G>A
ENST00000638587.1:c.1159G>A
ENST00000374574.2:c.1228G>A
ENST00000374580.8:c.1228G>A
NM_001204.6:c.1228G>A
More

Likely Pathogenic

Met criteria codes 4
PS1_Moderate PP3 PM2_Supporting PM1_Strong
Not Met criteria codes 5
BS1 BP4 PS4 PM5 BA1

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 BMPR2 c.1228G>A variant is a missense variant predicted to cause a glycine to arginine substitution at amino acid position 410. The variant is absent from gnomAD v2.1.1 control and v4.1.0 populations (PM2_supporting). Gly410Arg is located in the catalytic kinase domain and Gly410 is a known critical residue (PM1_strong). The variant was reported in two manuscripts (PMID: 26387786 and PMID: 21737554) describing the same individual; no other probands with the variant were identified (PS4 not met). A different variant affecting the same amino acid, c.1228 G>C (p.Gly410Arg), has been reported and was classified by our expert panel as likely pathogenic (PS1_moderate). Other pathogenic missense variants causing a different amino acid change at the same residue have not been reported (PM5 is not met). The REVEL score is 0.984, which meets the ClinGen Pulmonary Hypertension VCEP pathogenicity threshold of >=0.75 (PP3 met, BP4 not met). Criteria not evaluated included PP1, PM6, and PS2 due to the absence of segregation data. Functional data was not available (BS3 and PS3 not evaluated). In summary, this variant meets the criteria to be classified as likely pathogenic (LP) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS1_moderate, PM1_strong, PM2_supporting, and PP3 (VCEP specification version 1.1, 1/18/2024).
Met criteria codes
PS1_Moderate
The same amino acid change was reported in ClinVar (c.1228G>C) and was classified by the Pulmonary Hypertension VCEP as likely pathogenic.
PP3
REVEL score is 0.984, which meets the ClinGen Pulmonary Hypertension VCEP threshold for pathogenicity (>=0.75).
PM2_Supporting
The variant is absent from gnomAD v2.1.1 control and v4.1.0 populations. This criterion is applied at the supporting level, based on the specifications of the ClinGen Pulmonary Hypertension VCEP.
PM1_Strong
The variant is located in the conserved catalytic kinase domain and affects a known critical residue.
Not Met criteria codes
BS1
The variant is absent from gnomAD v2.1.1 control and v4.1.0 populations.
BP4
REVEL score is 0.984, which does not meet the ClinGen Pulmonary Hypertension VCEP threshold for non-pathogenicity (<=0.25).
PS4
The variant was reported in two manuscripts, but they described the same patient. The evidence does not meet the specifications described by the ClinGen PH-VCEP for this criterion.
PM5
No previous different missense change determined to be pathogenic.
BA1
The variant is absent from gnomAD v2.1.1 control and v4.1.0 populations.
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.