Submissions for variant NM_001204.7(BMPR2):c.377A>G (p.Asn126Ser)

dbSNP: rs863223426

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198552	SCV000249649	pathogenic	not provided	2014-09-03	criteria provided, single submitter	clinical testing	p.Asn126Ser (AAC>AGC): c.377 A>G in exon 3 of the BMPR2 gene (NM_001204.6). The N126S mutation in the BMPR2 gene has been reported previously in three unrelated individuals with a diagnosis of PAH (Machado R et al., 2009; Girerd B et al., 2010). This substitution occurs at a position that is completely conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Mutations in nearby residues (C118Y, C118W, C123S, C123R, N124D) have been reported in association with PAH, further supporting the functional importance of this region of the protein. Furthermore, the N126S mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, N126S in the BMPR2 gene is interpreted as a disease-causing mutation. This variant was found in PAH-ARRHYTHMIA
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376542	SCV001374103	likely pathogenic	Primary pulmonary hypertension	2022-11-15	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BMPR2 protein function. ClinVar contains an entry for this variant (Variation ID: 212817). This missense change has been observed in individuals with pulmonary arterial hypertension (PMID: 19555857, 20534176, 21737554, 29843651, 31727138, 32581362). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 126 of the BMPR2 protein (p.Asn126Ser).
Rare Disease Genomics Group, St George's University of London	RCV000488669	SCV000576053	pathogenic	Pulmonary hypertension, primary, 1		no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003667	SCV001162110	pathogenic	Pulmonary arterial hypertension		no assertion criteria provided	research
Wendy Chung Laboratory, Columbia University Medical Center	RCV001823880	SCV002073584	not provided	Pulmonary arterial hypertension; Idiopathic and/or familial pulmonary arterial hypertension		no assertion provided	literature only