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.1220A>C (p.Tyr407Ser)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA350341886

425895 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 06fc6939-a4d4-4983-a3d1-9e886ac9e5ea

Approved on: 2025-01-03

Published on: 2025-01-03

HGVS expressions

NM_001204.7:c.1220A>C

NM_001204.7(BMPR2):c.1220A>C (p.Tyr407Ser)

NC_000002.12:g.202532676A>C

CM000664.2:g.202532676A>C

NC_000002.11:g.203397399A>C

CM000664.1:g.203397399A>C

NC_000002.10:g.203105644A>C

NG_009363.1:g.161350A>C

ENST00000374580.10:c.1220A>C

ENST00000638587.1:c.1151A>C

ENST00000374574.2:c.1220A>C

ENST00000374580.8:c.1220A>C

NM_001204.6:c.1220A>C

Uncertain Significance

PP3 PM2_Supporting PM1

BP4 PS4 BA1 BS1 BS2

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 c.1220A>C (p. Tyr407Ser) variant is a missense variant located in exon 9 of the BMPR2 gene, predicted to cause substitution of tyrosine to serine at amino acid position 407. The variant is present in the conserved catalytic kinase domain but without functional evidence indicating a critical or non-critical amino acid residue (PM1_moderate). The variant is absent from gnomAD v2.1.1 controls and v4.1 (PM2_supporting). The REVEL prediction algorithm score is 0.981 and AlphaMissense is 0.9904 indicating pathogenicity (PP3_met). The variant has been reported in only one individual with PAH (PMID: 26387786) (PS4 not met). PS2 was not assessed due to lack of paternity data. No functional studies have been conducted for this variant (PS3 not assessed). 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: PM1_moderate, PM2_supporting, PP3_supporting (VCEP specification version 1.1.0, 1/18/2024).

PP3

The REVEL score is 0.981 which is above the pathogenicity threshold of ≥0.75, and the alpha missense score of 0.9904 predicted to be likely pathogenic.

PM2_Supporting

Variant is absent from gnomAD v2.1.1 controls and v4.1.

PM1

Variant changes an amino acid in the kinase domain but without functional evidence indicating critical or non-critical.

BP4

The REVEL score is 0.981 which is above the pathogenicity threshold of ≥0.75, and the alpha missense score of 0.9904 predicted to be likely pathogenic.

PS4

The variant has been reported in a single PAH patient (PMID: 26387786).

BA1

Variant is absent from gnomAD v2.1.1 controls and v4.1.

BS1

Variant is absent from gnomAD v2.1.1 controls and v4.1.

BS2

Variant absent in gnomAD v2.1.1, v4.1

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.