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]

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Variant: NM_001204.7(BMPR2):c.901T>C (p.Ser301Pro)

CA10576586

228460 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 35456c4e-ef26-4ca0-902b-0d0270033b01

HGVS expressions

NM_001204.7:c.901T>C

NM_001204.7(BMPR2):c.901T>C (p.Ser301Pro)

NC_000002.12:g.202520135T>C

CM000664.2:g.202520135T>C

NC_000002.11:g.203384858T>C

CM000664.1:g.203384858T>C

NC_000002.10:g.203093103T>C

NG_009363.1:g.148809T>C

ENST00000374580.10:c.901T>C

ENST00000638587.1:c.832T>C

ENST00000374574.2:c.901T>C

ENST00000374580.8:c.901T>C

NM_001204.6:c.901T>C

Pathogenic

PM6 PS4 PS3 PM1 PM2_Supporting

BA1 BP4 BS2 BS1 PP3

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.901T>C variant (NM_001204.7) in BMPR2 is a missense variant predicted to cause substitution of serine by proline at amino acid 301 (p.Ser301Pro). The variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting). The variant has been identified in 5 probands, meeting the PH VCEP threshold for PS4 (>4 pro bands; PMIDs 16429395, 18356561, 25917481, 29743074, and PH VCEP internal lab contributors). The variant has been identified as a de novo occurrence in one individual with pulmonary arterial hypertension and unconfirmed parental relationships (PM6; PMID 29743074). Immunostaining in Hela cells transfected with a FLAG-tagged c.901C>T BMPR2 expression construct demonstrated impaired subcellular trafficking of BMPRII (PMID: 25688877) and Western-blot analysis of pulmonary artery smooth muscle cells isolated from a patient with the c.901C>T variant showed no BMP4-induced phosphorylation of Smad1/5/8 (PMID: 19324947), indicating an effect on protein function (PS3). This variant resides in a conserved kinase domain (amino acids 203 – 504) but is not defined as a critical residue by the ClinGen PH VCEP (PM1_moderate). In summary, this variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP (specification version 1.0): PS4, PM6, PM2_Supporting, PS3, PM1_moderate).

PM6

This variant has been identified as a de novo occurrence with unconfirmed parental relationships in one individual with pulmonary arterial hypertension (PM6; PMID 29743074)

PS4

This variant has been reported in 5 probands meeting pulmonary arterial hypertension (PS4 ; PMIDs 16429395, 18356561, 25917481, 29743074, Internal lab contributors).

PS3

Immunostaining in Hela cells transfected with FLAG-tagged BMPR2 expression construct harboring the c.901C>T variant showed that this variant affect partially the subcellular trafficking of BMPRII (PMID: 25688877). Western-blot analysis using pulmonary artery smooth muscle cells isolated from a patient carrying the c.901C>T variant showed no BMP4-induced phosphorylation of Smad1/5/8 (PMID: 19324947). These results indicate that this variant impacts protein function (PS3).

PM1

This variant resides within a region (Kinase domain, amino acids 203 – 504), of BMPR2. However it was only scored for PM1_moderate because the variant was not specified as critical or not critical for protein function as defined by the ClinGen Pulmonary Hypertension VCEP.

PM2_Supporting

This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting).

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP4

The computational predictor REVEL gives a score of 0.451, which is neither above nor below the thresholds predicting a damaging or benign impact on BMPR2 function.

BS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP3

The computational predictor REVEL gives a score of 0.451, which is neither above nor below the thresholds predicting a damaging or benign impact on BMPR2 function.

Approved on: 2024-05-03

Published on: 2024-05-03

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