ClinVar Miner

Submissions for variant NM_001204.7(BMPR2):c.1472G>A (p.Arg491Gln)

dbSNP: rs137852749
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001810840 SCV000602648 pathogenic not provided 2019-08-28 criteria provided, single submitter clinical testing The BMPR2 c.1472G>A; p.Arg491Gln variant (rs137852749) is reported in the literature in multiple individuals affected with familial and sporadic forms of pulmonary arterial hypertension (PAH) (Deng 2000, Liu 2012, Machado 2006, Pfarr 2011, Rosenzweig 2008, Sztrymf 2008). This variant is reported as pathogenic in ClinVar (Variation ID: 8806), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 491 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional assays show that while the variant protein is trafficked appropriately to the plasma membrane, there is a decrease in ligand-dependent activation of a downstream SMAD reporter (Rudarakanchana 2002). Additionally, another variant at this codon (c.1471C>T, p.Arg491Trp) has been reported in individuals with PAH (Deng 2000, Liu 2012, Machado 2006, Pfarr 2011, Rosenzweig 2008, Sztrymf 2008), and codon 491 is considered a mutational hotspot (Wong 2006). Based on available information, this variant is considered to be pathogenic. References: Deng et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000; 67(3): 737-744. Liu D et al. Molecular genetics and clinical features of Chinese idiopathic and heritable pulmonary arterial hypertension patients. Eur Respir J. 2012 Mar;39(3):597-603. Machado et al. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat. 2006; 27(2): 121-132. Pfarr N et al. Hemodynamic and clinical onset in patients with hereditary pulmonary arterial hypertension and BMPR2 mutations. Respir Res. 2011 Jul 29;12:99. Rosenzweig et al. Clinical implications of determining BMPR2 mutation status in a large cohort of children and adults with pulmonary arterial hypertension. J Heart Lung Transplant. 2008; 27(6): 668-674. Rudarakanchana et al. Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum Mol Genet. 2002; 11(13): 1517-1525. Sztrymf et al. Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. Am J Respir Crit Care Med. 2008; 177(12): 1377-1383. Wong et al. Evolutionary conservation and mutational spectrum of BMPR2 gene. Gene. 2006; 368: 84-93.
Invitae RCV001851761 SCV002247293 pathogenic Primary pulmonary hypertension 2023-06-07 criteria provided, single submitter clinical testing 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. ClinVar contains an entry for this variant (Variation ID: 8806). This missense change has been observed in individual(s) with primary pulmonary hypertension (PMID: 10903931, 32581362). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 491 of the BMPR2 protein (p.Arg491Gln). This variant disrupts the p.Arg491 amino acid residue in BMPR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10903931, 12045205, 28388887, 31727138; 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.
3billion RCV003313915 SCV004013611 pathogenic Pulmonary venoocclusive disease 1, autosomal dominant criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 0.55). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008806 / PMID: 10903931). Different missense changes at the same codon (p.Arg491Leu, p.Arg491Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008802, VCV001067745 / PMID: 10903931). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM RCV000009351 SCV000029569 pathogenic Pulmonary hypertension, primary, 1 2000-09-01 no assertion criteria provided literature only
Rare Disease Genomics Group, St George's University of London RCV000009351 SCV000576250 pathogenic Pulmonary hypertension, primary, 1 no assertion criteria provided literature only
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003726 SCV001162169 pathogenic Pulmonary arterial hypertension no assertion criteria provided research
Wendy Chung Laboratory, Columbia University Medical Center RCV001823869 SCV002073644 not provided Pulmonary arterial hypertension; Idiopathic and/or familial pulmonary arterial hypertension no assertion provided literature only

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