Submissions for variant NM_001204.7(BMPR2):c.1471C>T (p.Arg491Trp)

dbSNP: rs137852746

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493405	SCV000582363	pathogenic	not provided	2023-04-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant inhibits Smad pathway activation and leads to disruption of other downstream signalling pathways (Rudarakanchana et al., 2002); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27587546, 21737554, 32634488, 35346192, 32581362, 19324947, 25688877, 27811071, 29843651, 28388887, 29743074, 30578397, 26387786, 14985116, 20002458, 15591269, 16429395, 11502704, 12045205, 20534176, 18356561, 15059534, 16002577, 10903931, 18503968, 31727138, 32966279, 33066286, 21801371)
John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine	RCV001003725	SCV002575048	pathogenic	Pulmonary arterial hypertension	2022-09-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002512939	SCV003524968	pathogenic	Primary pulmonary hypertension	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 491 of the BMPR2 protein (p.Arg491Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pulmonary hypertension (PMID: 10903931, 28388887). ClinVar contains an entry for this variant (Variation ID: 8802). 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) performed at Invitae indicates that this missense variant is expected to disrupt BMPR2 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg491 amino acid residue in BMPR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000009347	SCV000029565	pathogenic	Pulmonary hypertension, primary, 1	2000-09-01	no assertion criteria provided	literature only
Center for Genomic Medicine, Kyoto University Graduate School of Medicine	RCV000009347	SCV000320702	pathogenic	Pulmonary hypertension, primary, 1	2016-07-11	no assertion criteria provided	clinical testing
Rare Disease Genomics Group, St George's University of London	RCV000009347	SCV000576249	pathogenic	Pulmonary hypertension, primary, 1		no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003725	SCV001162168	pathogenic	Pulmonary arterial hypertension		no assertion criteria provided	research
Wendy Chung Laboratory, Columbia University Medical Center	RCV001823867	SCV002073643	not provided	Pulmonary arterial hypertension; Idiopathic and/or familial pulmonary arterial hypertension		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004549350	SCV004109284	pathogenic	BMPR2-related disorder	2024-03-21	no assertion criteria provided	clinical testing	The BMPR2 c.1471C>T variant is predicted to result in the amino acid substitution p.Arg491Trp. This variant has been reported in patients with pulmonary arterial hypertension (PAH) (e.g., Liu et al. 2011. PubMed ID: 21737554; Ghigna et al. 2016. PubMed ID: 27811071; Yang et al. 2018. PubMed ID: 29743074; Wang et al. 2019. PubMed ID: 30578397, see Supplementary Dataset 1). An alternate substitution of the same amino acid (p.Arg491Gln) has also been reported in PAH patients (Liu et al. 2011. PubMed ID: 21737554). The p.Arg491 amino acid is located in the BMPR2 kinase domain, and alterations of this amino acid have been reported to disrupt downstream signaling (Rudarakanchana et al. 2002. PubMed ID: 12045205; Dewachter et al. 2009. PubMed ID: 19324947). This variant has not been reported in the literature or in a large population database, indicating it is rare. Several outside laboratories have interpreted this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/8802/). This variant is interpreted as pathogenic.