Submissions for variant NM_001204.7(BMPR2):c.1516A>G (p.Met506Val)

gnomAD frequency: 0.00004  dbSNP: rs370457339

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen	RCV004551612	SCV005043320	uncertain significance	Pulmonary arterial hypertension	2024-05-01	reviewed by expert panel	curation	The BMPR2 c.1516A>G variant is a missense variant predicted to cause substitution of methionine to valine at amino acid position 506 ((p.(Met506Val)). The highest population minor allele frequency is for East Asian (0.00022) in gnomAD v2.1.1 controls and 0.00015 in gnomAD v3.1.2 and does not meet population criteria (PM2 <0.01%, BS1 >0.1%, anBA1 >1%). BP4 is met by the computational predictor REVEL score of 0.23, which is below the PH-VCEP specified threshold of <0.25 (additional support for BP4 is alpha missense score of 0.077). This variant does not reside within the critical extracellular or kinase domains, so PM1 is not met. Co-segregation/case and experimental criteria was not evaluated due to lack of reported evidence. Alternative variants in the same amino acid have not been reported. In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BP4 (VCEP specification version 1.1, 1/18/2024).
Johns Hopkins Genomics, Johns Hopkins University	RCV001263471	SCV001441547	uncertain significance	Pulmonary venoocclusive disease 1	2020-10-28	criteria provided, single submitter	clinical testing	This BMPR2 variant (rs370457339) is rare (<0.1%) in a large population dataset (gnomAD: 11/251490 total alleles; 0.004%; no homozygotes) and has not been reported in the literature, to our knowledge. This variant has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be tolerated, and the methionine residue at this position is evolutionarily conserved across most mammals. Due to insufficient evidence, we consider the clinical significance of c.1516A>G to be uncertain at this time.
Fulgent Genetics, Fulgent Genetics	RCV002489189	SCV002783359	uncertain significance	Pulmonary hypertension, primary, 1; Pulmonary venoocclusive disease 1	2022-02-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002527016	SCV003028024	likely benign	Primary pulmonary hypertension	2024-02-07	criteria provided, single submitter	clinical testing
Rare Disease Genomics Group, St George's University of London	RCV000488616	SCV000576256	uncertain significance	Pulmonary hypertension, primary, 1		no assertion criteria provided	literature only