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.1178A>G (p.Asn393Ser)

CA350341785

812825 (ClinVar)

Gene: BMPR2 (HGNC:659)

Condition: pulmonary arterial hypertension (MONDO:0015924)

Inheritance Mode: Autosomal dominant inheritance

UUID: e098d725-2e47-436a-91f1-bdbf8009f446

Approved on: 2025-01-03

Published on: 2025-01-03

HGVS expressions

NM_001204.7(BMPR2):c.1178A>G (p.Asn393Ser)

NM_001204.7:c.1178A>G

NC_000002.12:g.202532634A>G

CM000664.2:g.202532634A>G

NC_000002.11:g.203397357A>G

CM000664.1:g.203397357A>G

NC_000002.10:g.203105602A>G

NG_009363.1:g.161308A>G

ENST00000374580.10:c.1178A>G

ENST00000638587.1:c.1109A>G

ENST00000374574.2:c.1178A>G

ENST00000374580.8:c.1178A>G

NM_001204.6:c.1178A>G

Uncertain Significance

PM2_Supporting PM1

BA1 BP4 BS1 PP3 PM4 PS4 PVS1

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.1178A>G (p.Asn393Ser) variant is a missense variant harboured in exon 9 of the BMPR2 gene, predicted to cause substitution of asparagine to serine encoding the functionally relevant catalytic kinase domain but without functional evidence indicating critical or non-critical (PM1_moderate). This variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting). The REVEL prediction algorithm score is 0.68, AlphaMissense is 0.79, both below our thresholds for pathogenicity (PP3_not met) but above our thresholds for benignity (BP4 not met). The variant has been reported only once in a PAH subject (PMID: 32581362) (PS4 not met). Functional studies have not been conducted for this variant (PS3 not assessed). In summary, this variant meets the criteria to be classified as a variant of unknown significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM2_supporting (VCEP specification version 1.1.0, 1/18/2024).

PM2_Supporting

The variant is absent from gnomAd v2.1.1 controls and v4.1.

PM1

p.Asn393Ser is located in the catalytic kinase domain without benign variation.

BA1

The variant is absent from gnomAd v2.1.1 controls and v4.1.

BP4

The REVEL score of 0.68 is bellow the PH VCEP threshold of >=0.75 for pathogenicity and above the threshold of <=0.25 for benignity.

BS1

The variant is absent from gnomAd v2.1.1 controls and v4.1.

PP3

The REVEL score of 0.68 is bellow the PH VCEP threshold of >=0.75 for pathogenicity and above the threshold of <=0.25 for benignity.

PM4

The variant is a missense variant.

PS4

The variant has been identified in a single individual diagnosed with PAH (PMID: 32581362).

PVS1

The variant is a missense variant.

Curation History

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