Submissions for variant NM_001204.7(BMPR2):c.86A>G (p.Asn29Ser)

gnomAD frequency: 0.00241  dbSNP: rs112862820

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen	RCV004720254	SCV005331521	likely benign	Pulmonary arterial hypertension	2024-09-10	reviewed by expert panel	curation	The BMPR2 c.86A>G missense variant is predicted to cause a substitution of asparagine to serine at amino acid position 29 (p.Asn29Ser) in exon 2 within the signal peptide domain. The highest population minor allele frequency in gnomAD v2.1.1 controls is 0.006265 (v4.1.0 is 0.007668) in African/African American population, which is higher than the ClinGen Pulmonary Hypertension VECP threshold ≥0.1% for BS1, and therefore meets this criterion. The computational predictor REVEL gives a score of 0.497 indicating neither PP3 (≥0.75) nor BP4 (≤0.25) met. SpliceAI algorithm predicts no deleterious effect on acceptor or donor splice site. In summary, the variant meets the criteria to be classified as variant of likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1 (VCEP specification version 1.1, 1/18/2024).
Illumina Laboratory Services, Illumina	RCV000389962	SCV000426383	benign	Pulmonary hypertension, primary, 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001507195	SCV000560771	benign	Primary pulmonary hypertension	2023-11-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002374565	SCV002684601	uncertain significance	Inborn genetic diseases	2023-11-06	criteria provided, single submitter	clinical testing	The p.N29S variant (also known as c.86A>G), located in coding exon 2 of the BMPR2 gene, results from an A to G substitution at nucleotide position 86. The asparagine at codon 29 is replaced by serine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004549757	SCV004758676	likely benign	BMPR2-related disorder	2021-02-15	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).