ClinVar Genomic variation as it relates to human health

The NM_001204.7(BMPR2):c.1472G>A (p.Arg491Gln) variant is a missense variant predicted to cause an arginine to glutamine substitution at amino acid position 491. The variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting). The variant co-segregated with PAH in a large Iberian family with at least four confirmed meioses (PP1; PMID: 30894412), is recurrent in more than four unrelated PAH patients (PS4; PMID: 20534176 and PMID: 29023671) and confirmed de novo in at least two probands with unaffected parents (PS2; PMID: 10903931 and PMID: 23298310). c.1472G>A resides in the conserved kinase domain of BMPR-II and changes an invariant and critical arginine residue at position 491 (PM1_Strong; PMID: 7768349, PMID: 34400635), likely impairing interaction with other BMP receptors. The functional assay evidence for a role in BMP receptor interactions was based on a PH VCEP approved luciferase activity assay but lacked known pathogenic and benign variant controls, so PS3 was scored at the supporting level (PS3_supporting; PMID: 18321866). A different amino acid change at the same position (p.Arg491Trp) was classified as pathogenic (PM5). PP3 was met based on a REVEL score of 0.962. In summary, this variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS2, PS3_supporting, PS4, PM1_strong, PM2_supporting, PM5, PP1, PP3 (VCEP specification version v 1.1, 1/18/2024).

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.

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.

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.