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.1424C>A (p.Ser475Ter)

CA350344424

425943 (ClinVar)

Gene: BMPR2
Condition: pulmonary arterial hypertension
Inheritance Mode: Autosomal dominant inheritance
UUID: e689411a-9ea5-436f-ad52-c1b1bd9b8ae1
Approved on: 2024-05-03
Published on: 2024-05-03

HGVS expressions

NM_001204.7:c.1424C>A
NM_001204.7(BMPR2):c.1424C>A (p.Ser475Ter)
NC_000002.12:g.202552726C>A
CM000664.2:g.202552726C>A
NC_000002.11:g.203417449C>A
CM000664.1:g.203417449C>A
NC_000002.10:g.203125694C>A
NG_009363.1:g.181400C>A
ENST00000374580.10:c.1424C>A
ENST00000638587.1:c.1355C>A
ENST00000374574.2:c.1424C>A
ENST00000374580.8:c.1424C>A
NM_001204.6:c.1424C>A
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Pathogenic

Met criteria codes 3
PVS1 PS4_Supporting PM2_Supporting
Not Met criteria codes 2
BA1 BS1

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.1424C>A variant is a nonsense mutation in the kinase domain (exon 11 of 13). It is predicted to result in nonsense mediated mRNA decay, and therefore meets the criteria for PVS1. It is absent from gnomAD v2.1.1 (all samples), meeting PM2_supporting. There are three reports of this variant in the literature (PMIDs 16429395, 20534176 and 32581362). However, since PMID 16429395 summarized data from multiple countries, including the UK and French populations that were the subject of the later papers, it is not possible to determine if all three probands are independent. Thus conservatively, only counted 2 probands were counted (PS4_supporting). In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1, PM2_supporting, PS4_supporting (VCEP specification version 1.1, 1/18/2024).
Met criteria codes
PVS1
Truncating variant in the kinase domain, predicted to undergo NMD.
PS4_Supporting
Present in >1 probands.
PM2_Supporting
Absent in gnomAD v2.1.1.
Not Met criteria codes
BA1
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
Curation History
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