Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001204.7(BMPR2):c.1175T>C (p.Val392Ala)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA350341779

425889 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

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

Uncertain Significance

PM2_Supporting PP3 PM1

PS4 BA1 BS1 BS2 BP4

Evidence Links 0

Expert Panel

Pulmonary Hypertension VCEP

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).

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)

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

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.