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.1019T>C (p.Leu340Pro)

CA350341382

425864 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 2e2cb93e-28ce-44fe-bca0-ce623262cce9

Approved on: 2024-09-20

Published on: 2024-09-20

HGVS expressions

NM_001204.7:c.1019T>C

NM_001204.7(BMPR2):c.1019T>C (p.Leu340Pro)

NC_000002.12:g.202530845T>C

CM000664.2:g.202530845T>C

NC_000002.11:g.203395568T>C

CM000664.1:g.203395568T>C

NC_000002.10:g.203103813T>C

NG_009363.1:g.159519T>C

ENST00000374580.10:c.1019T>C

ENST00000638587.1:c.950T>C

ENST00000374574.2:c.1019T>C

ENST00000374580.8:c.1019T>C

NM_001204.6:c.1019T>C

Uncertain Significance

PP3 PM1 PM2_Supporting PS4_Supporting

PS1 PM5 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 BMPR2 c.1019T>C (p.Leu340Pro) variant is an exonic variant which is located in exon 8. This variant is absent from gnomAD v2.1.1 controls and v4.1 (PM2_supporting met). The variant is located in a well-established protein kinase domain (PM1_met) and has been identified in 3 apparently unrelated individuals with PAH to date (PMIDs 18356561, 19555857, 32581362; PS4_supporting met). In silico prediction is consistent with a pathogenic effect ((REVEL score 0.980 (>0.75; PP3 met)). PP1 was not assessed due to absence of co-segregation data. No other missense variants at the same amino acid have been reported for pulmonary arterial hypertension (PS1, PM5 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, PM2_supporting, PP3, PS4_supporting (VCEP specification version 1.1.0, 1/18/2024).

PP3

REVEL score: 0.980. SpliceAI score: 0.01 (benign)

PM1

Variant present in established Kinase domain

PM2_Supporting

Variant absent from gnomAD

PS4_Supporting

PS4_supp: met (+1). Three independent patients. PMID 18356561 (Sztrymf et al., 2008; French PH network): 1 patient (IPAH/HPAH) PMID 19555857 (Machado et al., 2009): 1 HPAH patient PMID 32581362 (Turro et al, 2020) WGS study (1 PAH patient E010683, supplemental data). No segregation or functional data present to date (11-09-2024)

PS1

No reported pathogenic variants for p.Leu340

PM5

No reported pathogenic variants for p.Leu340

PVS1

Missense variant with no apparent effect on splicing (SpliceAi score 0.01)

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