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.1016T>A (p.Val339Asp)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA350341378

425863 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0efa5eda-89d2-4f02-bd03-05d9e86ebba1

Approved on: 2024-11-06

Published on: 2024-11-06

HGVS expressions

NM_001204.7:c.1016T>A

NM_001204.7(BMPR2):c.1016T>A (p.Val339Asp)

NC_000002.12:g.202530842T>A

CM000664.2:g.202530842T>A

NC_000002.11:g.203395565T>A

CM000664.1:g.203395565T>A

NC_000002.10:g.203103810T>A

NG_009363.1:g.159516T>A

ENST00000374580.10:c.1016T>A

ENST00000638587.1:c.947T>A

ENST00000374574.2:c.1016T>A

ENST00000374580.8:c.1016T>A

NM_001204.6:c.1016T>A

Uncertain Significance

PS4_Supporting PP3 PM1 PM2_Supporting

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.1016T>A (p.Val339Asp) variant is harboured in exon 8 of the gene, encoding the functionally relevant catalytic kinase domain (PM1_met). The variant has been twice reported in the Japanese population in one IPAH and one HPAH subject (PMID: 23579436 and PMID: 23675998), (PS4_supporting). This variant is absent from gnomAD v2.1.1 (controls) and v4.1.0 (PM2_supporting). The REVEL prediction algorithm score is 0.967, AlphaMissense is 0.9992 indicating pathogenicity (PP3_met). PP1 and PS2 were not assessed due to absence of co-segregation data and parental data respectively. No other amino acid change at the same position has been reported for PAH (PS1 and PM5 not assessed). Functional studies have not been conducted for this variant (PS3 not assessed). In summary, this variant meets the criteria to be classified as VUS for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1, PM2_supporting, PP3, PS4_supporting (VCEP specification version 1.1.0, 1/18/2024).

PS4_Supporting

The p.Val339Asp variant has been reported in one IPAH and one HPAH patient from the Japanese population (PMIDs: 23579436, 23675998).

PP3

Variant has a REVEL score of 0.967, which meets the criteria for indicated pathogenicity (≥0.75).

PM1

Variant is located in the functionally relevant catalytic kinase domain.

PM2_Supporting

Variant is absent from gnomAD v2.1.1 and 4.1.0

BP4

Variant has a REVEL score of 0.967, which exceeds the threshold for indicated benignity (≤0.25).

Curation History

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