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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Variant: NM_001204.7(BMPR2):c.1037C>A (p.Thr346Asn)

CA2061282

1112108 (ClinVar)

Gene: BMPR2
Condition: pulmonary arterial hypertension
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: bdcf5719-90c7-4cdb-863e-6a5c7230b922

HGVS expressions

NM_001204.7:c.1037C>A
NM_001204.7(BMPR2):c.1037C>A (p.Thr346Asn)
NC_000002.12:g.202530863C>A
CM000664.2:g.202530863C>A
NC_000002.11:g.203395586C>A
CM000664.1:g.203395586C>A
NC_000002.10:g.203103831C>A
NG_009363.1:g.159537C>A
ENST00000374580.10:c.1037C>A
ENST00000638587.1:c.968C>A
ENST00000374574.2:c.1037C>A
ENST00000374580.8:c.1037C>A
NM_001204.6:c.1037C>A

Likely Benign

Met criteria codes 3
PM1 BS1 BP4
Not Met criteria codes 4
PS4 BA1 PP3 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 missense variant c.1037C>A (p.Thr346Asn) is located in exon eight. This variant has been found with a frequency of 0.00006 in gnomAD version2.1.1 controls, although it is present above 0.1% in Ashkenazi Jewish (0.159%, 16/10,078 total alleles) (BS1_met). The variant is predicted to have no effect on protein function with REVEL score of 0.239, which meets the threshold for BP4 (<0.25). No effect on splicing predicted as SpliceAI score is 0. The missense change is located within the conserved kinase domain but there are no functional data to support the amino acid residue as critical or non-critical (PM1_met with no upgrade). In summary, the 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, BP4, PM1 (VCEP specification version 1.1, 1/18/2024).
Met criteria codes
PM1
Variant is located within the conserved kinase domain, in which many causative variants have been reported, but there is no functional data available indicating critical or non-critical residue. Thus, scored as moderate without upgrade to strong.
BS1
Allele frequency in Ashkenazi Jewish sub-population (gnomAD v2.1.1 controls) is 0.001640, which is >0.1%.
BP4
REVEL score is 0.239, which is below the threshold of 0.25 to meet the BP4 criterion. Additionally, no effect on splicing predicted by SpliceAI score of 0.
Not Met criteria codes
PS4
Not evaluated
BA1
Allele frequency in Ashkenazi Jewish sub-population (gnomAD v2.1.1 controls) is 0.001640, which is <5%.
PP3
BP4 met
PM2
Allele frequency in Ashkenazi Jewish sub-population (gnomAD v2.1.1 controls) is 0.001640.
Approved on: 2024-05-01
Published on: 2024-05-01
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