Variant: NM_001204.7(BMPR2):c.2186G>C (p.Gly729Ala)

CA2061499

993809 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

UUID: 6f97c76c-3edf-402f-9000-aef4af619d77

Approved on: 2024-05-03

Published on: 2024-05-03

HGVS expressions

NM_001204.7:c.2186G>C
NM_001204.7(BMPR2):c.2186G>C (p.Gly729Ala)
NC_000002.12:g.202555851G>C
CM000664.2:g.202555851G>C
NC_000002.11:g.203420574G>C
CM000664.1:g.203420574G>C
NC_000002.10:g.203128819G>C
NG_009363.1:g.184525G>C
ENST00000374580.10:c.2186G>C
ENST00000638587.1:c.2117G>C
ENST00000374574.2:c.1586+2963G>C
ENST00000374580.8:c.2186G>C
NM_001204.6:c.2186G>C

Likely Benign

• Met criteria codes: BS1

• Not Met criteria codes: PS1 BA1 PP3 PM2 PM1 PM5 BP4

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 NM_001204.7(BMPR2) c.2186G>C variant is a missense variant predicted to cause substitution of glycine by alanine at amino acid 729 (p.Gly729Ala). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.001639 (21/12810 alleles) in Swedish population, which is higher than the ClinGen PH VCEP threshold (>0.1%) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.36, which is neither above nor below the thresholds predicting a damaging or benign impact on BMPR2 function. In summary, this variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1. (VCEP specifications version 1.1, 1/18/2024)

Met criteria codes

• BS1: Allele frequency in the Swedish population (gnomAD v2.1.1 controls) is greater than 0.1% (MAF: 0.0016)

Not Met criteria codes

• PS1: Amino acid change has not been reported previously
• BA1: Allele frequency is less than 1% in controls
• PP3: REVEL score is 0.36 so does not meet the threshold to be classified as deleterious (REVEL >0.75)
• PM2: Variant allele is greater than 0.01% in controls (gnomAD v2.1.1)
• PM1: Located in a domain of undefined function
• PM5: Amino acid residue has not been previously reported as mutated
• BP4: REVEL score is 0.36 so does not meet the threshold to be classified as benign (REVEL <0.25)