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

Pathogenic

• Met criteria codes: PVS1 PM2_Supporting PS4_Supporting

• Not Met criteria codes: BA1 BS1

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

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.
• PM2_Supporting: Absent in gnomAD v2.1.1.
• PS4_Supporting: Present in >1 probands.

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