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]
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  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
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Variant: NM_001204.7(BMPR2):c.1481C>T (p.Ala494Val)

CA2061380

333645 (ClinVar)

Gene: BMPR2
Condition: pulmonary arterial hypertension
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 7cf9ea5c-6013-409f-9df8-4e4b68cbf8fb
Approved on: 2024-05-03
Published on: 2024-05-03

HGVS expressions

NM_001204.7:c.1481C>T
NM_001204.7(BMPR2):c.1481C>T (p.Ala494Val)
NC_000002.12:g.202552783C>T
CM000664.2:g.202552783C>T
NC_000002.11:g.203417506C>T
CM000664.1:g.203417506C>T
NC_000002.10:g.203125751C>T
NG_009363.1:g.181457C>T
ENST00000374580.10:c.1481C>T
ENST00000638587.1:c.1412C>T
ENST00000374574.2:c.1481C>T
ENST00000374580.8:c.1481C>T
NM_001204.6:c.1481C>T

Uncertain Significance

Met criteria codes 3
BS1 PP3 PM1
Not Met criteria codes 5
PS4 PS3 PS1 PM5 PM2

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.1481C>T variant is a missense variant predicted to result in an alanine to valine substitution at amino acid 494 (p.Ala494Val). The minor allele frequency in gnomAD v2.1.1 controls “Other East Asian" is 0.0016% (11/7044 alleles), which exceeds the PH VCEP threshold of >0.1% for BS1. The variant is located in the kinase domain of BMPR2 (amino acids 203-504) but there is no functional evidence for or against this residue being critical, thus meeting PM1 without modification. The REVEL score is 0.872, exceeding the threshold of 0.75 (PP3). In summary, the variant meets the criteria to be classified as uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1, PM1, PP3 (VCEP specification version 1.1, 1/18/2024).
Met criteria codes
BS1
The frequency in gnomAD v2.1.1 "Other East Asian" controls is 0.0016, exceeding the VCEP specification threshold of 0.1%.
PP3
REVEL score is 0.872, exceeding the threshold of 0.75.
PM1
Variant changes an amino acid in the kinase domain (aa 203-504) but without functional evidence indicating if it is critical or non-critical.
Not Met criteria codes
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No functional studies were identified for this variant.
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No other missense change has been reported at this residue.
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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