Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_001204.7(BMPR2):c.1126G>A (p.Glu376Lys)

CA350341606

977222 (ClinVar)

Gene: BMPR2
Condition: pulmonary arterial hypertension
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 1bf87321-26f3-4002-89f6-676c672578d4
Approved on: 2024-09-10
Published on: 2024-09-10

HGVS expressions

NM_001204.7:c.1126G>A
NM_001204.7(BMPR2):c.1126G>A (p.Glu376Lys)
NC_000002.12:g.202530952G>A
CM000664.2:g.202530952G>A
NC_000002.11:g.203395675G>A
CM000664.1:g.203395675G>A
NC_000002.10:g.203103920G>A
NG_009363.1:g.159626G>A
ENST00000374580.10:c.1126G>A
ENST00000638587.1:c.1057G>A
ENST00000374574.2:c.1126G>A
ENST00000374580.8:c.1126G>A
NM_001204.6:c.1126G>A
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Uncertain Significance

Met criteria codes 2
PM2 PM1
Not Met criteria codes 4
PP3 PM6 BP4 PS4

Evidence Links 0

Expert Panel

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.1126G>A (p.Glu376Lys) variant is an exonic variant located 3 base pairs before the end of exon 8. The variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_Supporting). The variant has not been reported in pulmonary arterial hypertension patients to date. The variant has been identified in a patient with progressive myositis ossificans and a patient with unknown phenotype (ClinVar ID 977222) (PS4_not met). The variant is located in the well-established kinase domain (PM1_met). However, protein and splice-site prediction algorithms do not predict pathogenicity ((REVEL score 0.47 (>0,25-<0.75); Splice AI score 0 (benign)) (PP3_not met, BP4_not met). PP1 was not evaluated due to absence of co-segregation data. No other missense variants at the same amino acid have been reported for PAH (PS1, PM5 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 (VCEP specification version 1.1.0, 1/18/2024).
Met criteria codes
PM2
Variant is absent from gnomAD (controls) v2.1.1 and v4.1
PM1
Variant is located in the well-established kinase domain. PM1_met
Not Met criteria codes
PP3
Protein and splice-site prediction algorithms do not predict pathogenic character (REVEL score 0.47 (<0.75); Splice AI score 0 (benign)). PP3_not met
PM6
No variants have been reported for pulmonary arterial hypertension.
BP4
Protein and splice-site prediction algorithms do not predict benign character (REVEL score 0.47 (>0.25); Splice AI score 0 (benign)). BP4_not met.
PS4
The variant has not been reported in PAH patients to date. The variant has been identified in a patient with progressive myositis ossificans and in a patient with unknown phenotype (ClinVar ID 977222) (PS4_not met).
Curation History
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