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]
  • 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.1157A>T (p.Glu386Val)

CA350341741

425887 (ClinVar)

Gene: BMPR2
Condition: pulmonary arterial hypertension
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 5fa5715b-b0db-4fa2-acc1-c29cb80d5dc3
Approved on: 2024-11-06
Published on: 2024-11-06

HGVS expressions

NM_001204.7:c.1157A>T
NM_001204.7(BMPR2):c.1157A>T (p.Glu386Val)
NC_000002.12:g.202532613A>T
CM000664.2:g.202532613A>T
NC_000002.11:g.203397336A>T
CM000664.1:g.203397336A>T
NC_000002.10:g.203105581A>T
NG_009363.1:g.161287A>T
ENST00000374580.10:c.1157A>T
ENST00000638587.1:c.1088A>T
ENST00000374574.2:c.1157A>T
ENST00000374580.8:c.1157A>T
NM_001204.6:c.1157A>T
More

Likely Pathogenic

Met criteria codes 4
PP3 PM1_Strong PM5_Supporting PM2_Supporting
Not Met criteria codes 2
BP4 PP1

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.1157A>T (p.Glu386Val) variant is harboured in exon 9 of the BMPR2 gene, encoding the functionally relevant catalytic kinase domain and impacts an amino acid indispensable to kinase structure and function (PM1_strong). This variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting). The variant has been reported once in an FPAH subject (PMID: 18364108) (PS4 not met). The REVEL prediction algorithm score is 0.99, the AlphaMissense score is 0.996 indicating pathogenicity (PP3_met). PS2 was not assessed due to lack of paternity data. Functional studies have not been conducted for this variant (PS3 not assessed). Four additional likely pathogenic variants (p.Glu386Ala/Gln/Gly/Lys) have been reported at the same position (PMIDs: 18503968, 21801371, 23675998 and 26387786) (PM5_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_strong, PM2_supporting, PM5_supporting, PP3 (VCEP specification version 1.1.0, 1/18/2024).
Met criteria codes
PP3
REVEL score is 0.99, which meets the ClinGen Pulmonary Hypertension VCEP cut-off of >0.75.
PM1_Strong
The variant is predicted to change a Glutamic Acid residue for a Valine in position 386. This change occurs in the Kinase Domain and changes an invariant residue. Therefore, we upgrade this criterion to a strong level.
PM5_Supporting
There are 4 additional missense changes reported in ClinVar that have been classified as pathogenic, including p.Glu386Lys, p.Glu386Gln, p.Glu386Gly, and p.Glu386Ala. Since it is likely that no adapted ACMG guidelines were used for the classification of these variants, we take a conservative approach and apply this criterion at the supporting level.
PM2_Supporting
The variant is absent from the gnomAD v2.1.1 controls and v4.1.0 populations. This criterion is applied at the supporting level, based on the specifications of the ClinGen Pulmonary Hypertension VCEP.
Not Met criteria codes
BP4
REVEL score is 0.99, which does not meet the ClinGen Pulmonary Hypertension VCEP cut-off of <0.25.
PP1
The variant cosegregated with PAH in a multigenerational Chinese family (probant (14 yrs old), his brother (4 yrs old). Their mother (32 yrs old) was not sequenced (PMID: 18364108).
Curation History
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