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.1175T>C (p.Val392Ala)

CA350341779

425889 (ClinVar)

Gene: BMPR2
Condition: pulmonary arterial hypertension
Inheritance Mode: Autosomal dominant inheritance
UUID: 8ce94f69-5d6f-4c30-bee8-b5174220c1f0
Approved on: 2024-11-06
Published on: 2024-11-06

HGVS expressions

NM_001204.7:c.1175T>C
NM_001204.7(BMPR2):c.1175T>C (p.Val392Ala)
NC_000002.12:g.202532631T>C
CM000664.2:g.202532631T>C
NC_000002.11:g.203397354T>C
CM000664.1:g.203397354T>C
NC_000002.10:g.203105599T>C
NG_009363.1:g.161305T>C
ENST00000374580.10:c.1175T>C
ENST00000638587.1:c.1106T>C
ENST00000374574.2:c.1175T>C
ENST00000374580.8:c.1175T>C
NM_001204.6:c.1175T>C
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Uncertain Significance

Met criteria codes 3
PM2_Supporting PP3 PM1
Not Met criteria codes 5
PS4 BA1 BS1 BS2 BP4

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 NM_001204.7(BMPR2) c.1175T>C (p.Val392Ala) variant is located in exon 9 of the BMPR2 gene and is absent from gnomAD v2.1.1 (controls) and v4.1.0 (PM2_supporting). The variant is located in the functionally relevant catalytic kinase domain (PM1_met) but is not a critical or non-critical residue. The variant has been reported in only one individual with IPAH (PMID: 21737554 and 20002458) (PS4 not met). The REVEL score for the variant is 0.954, which is greater than the PH VCEP threshold of >= 0.75, and the AlphaMissense score is 0.9795, indicating pathogenicity (PP3_met). No segregation or parental data were found (PP1 and PS2 not evaluated). No other amino acid change at the same position has been reported for PAH (PS1 and PM5 not evaluated). No functional evidence was found (PS3 not evaluated). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting, PM1, PP3 (VCEP specification version 1.1.0, 1/18/2024).
Met criteria codes
PM2_Supporting
Variant absent in GnomAD v 4.1.0
PP3
REVEL score is 0.954 which is ≥0.75 cutoff and alpha missense score of 0.9795, predicted to be likely pathogenic
PM1
Variant located within the kinase domain (aa203-504)
Not Met criteria codes
PS4
PMID: 21737554 and 20002458 refer to the variant in the same IPAH Chinese patient.
BA1
Variant absent in GnomAD v 4.1.0
BS1
Variant absent in GnomAD v 4.1.0
BS2
Variant absent in Gnomad v.4.1.0
BP4
REVEL score is 0.954 which is greater than 0.25
Curation History
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