Variant: NM_001204.7(BMPR2):c.1228G>C (p.Gly410Arg)

CA350341904

812827 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

UUID: cfb091bf-d2ca-4341-b8a0-19f154be590c

Approved on: 2025-01-03

Published on: 2025-01-03

HGVS expressions

NM_001204.7:c.1228G>C
NM_001204.7(BMPR2):c.1228G>C (p.Gly410Arg)
NC_000002.12:g.202532684G>C
CM000664.2:g.202532684G>C
NC_000002.11:g.203397407G>C
CM000664.1:g.203397407G>C
NC_000002.10:g.203105652G>C
NG_009363.1:g.161358G>C
ENST00000374580.10:c.1228G>C
ENST00000638587.1:c.1159G>C
ENST00000374574.2:c.1228G>C
ENST00000374580.8:c.1228G>C
NM_001204.6:c.1228G>C

Likely Pathogenic

• Met criteria codes: PM2_Supporting PM1_Strong PS4_Supporting PP3 PS1_Moderate

• Not Met criteria codes: PM5 BS1 BP4 BA1

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.1228G>C variant is a missense variant predicted to cause a glycine to arginine substitution at amino acid position 410 (p.Gly410Arg). The variant is absent from gnomAD v2.1.1 control and v4.1.0 populations (PM2_supporting). The variant was reported in one individual with pulmonary arterial hypertension in ClinVar and two affected twins (https://doi.org/10.1164/ajrccm-conference.2012.185.1_MeetingAbstracts.A6192) (PS4_supporting). Gly410Arg is located in the catalytic kinase domain and Gly410 is known to be an indispensable residue (PM1_strong). A different variant affecting the same amino acid, c.1228 G>A (p.Gly410Arg), has been reported and was classified by our expert panel as likely pathogenic (PS1_moderate). Other pathogenic missense variants causing a different amino acid change at the same residue have not been reported (PM5 not met). The REVEL score for this variant is 0.984, which meets the threshold of >=0.75 (PP3 met, BP4 not met). Criteria not evaluated included PP1, PM6, and PS2 due to the absence of segregation evidence, and BS3 and PS3 due to the lack of functional data. In summary, this variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS1_moderate, PS4_supporting, PM1_strong, PM2_supporting, and PP3 (VCEP specification version 1.1, 1/18/2024).

Met criteria codes

• PM2_Supporting: The variant is absent from gnomAD v2.1.1 control and v4.1.0 populations. This criterion is applied at the supporting level, based on the specifications of the ClinGen Pulmonary Hypertension VCEP.
• PM1_Strong: The variant is located in the conserved catalytic kinase domain and affects a known critical amino acid residue.
• PS4_Supporting: The variant has been reported in three individuals with PAH, including two unrelated probands (PMID: 32581362 and https://doi.org/10.1164/ajrccm-conference.2012.185.1_MeetingAbstracts.A6192), meeting the threshold of >1 individuals.
• PP3: REVEL score is 0.984, which meets the ClinGen Pulmonary Hypertension VCEP pathogenicity threshold of >=0.75.
• PS1_Moderate: A different variant affecting the same amino acid, c.1228 G>A (p.Gly410Arg), has been reported and was classified by our expert panel as likely pathogenic (PS1_moderate).

Not Met criteria codes

• PM5: No previous different missense change determined to be pathogenic.
• BS1: The variant is absent from gnomAD v2.1.1 control and v4.1.0 populations.
• BP4: REVEL score is 0.984, which is above the ClinGen Pulmonary Hypertension VCEP threshold of <=0.25.
• BA1: The variant is absent from gnomAD v2.1.1 control and v4.1.0 populations.