Submissions for variant NM_001204.7(BMPR2):c.961C>T (p.Arg321Ter)

dbSNP: rs1060502581

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376634	SCV000550169	pathogenic	Primary pulmonary hypertension	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg321*) in the BMPR2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BMPR2 are known to be pathogenic (PMID: 16429395). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with pulmonary hypertension (PMID: 15591269, 16429395, 21801371). ClinVar contains an entry for this variant (Variation ID: 409826). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001810954	SCV001156675	pathogenic	not provided	2019-09-04	criteria provided, single submitter	clinical testing	The BMPR2 c.961C>T; p.Arg321Ter variant (rs1060502581) is reported in the literature in multiple individuals and families affected with pulmonary arterial hypertension (Girerd 2010, Koehler 2004, Machado 2006, Pfarr 2011, Rosenzweig 2008, Sztrymf 2008, Wang 2016). This variant is reported as pathogenic in ClinVar (Variation ID: 409826), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. This prediction is supported by in vitro functional analyses, which show reduced transcript and protein levels (Drake 2011, Dunmore 2013). Based on available information, this variant is considered to be pathogenic. References: Drake KM et al. Altered MicroRNA processing in heritable pulmonary arterial hypertension: an important role for Smad-8. Am J Respir Crit Care Med. 2011 Dec 15;184(12):1400-8. Dunmore BJ et al. The lysosomal inhibitor, chloroquine, increases cell surface BMPR-II levels and restores BMP9 signalling in endothelial cells harbouring BMPR-II mutations. Hum Mol Genet. 2013 Sep 15;22(18):3667-79. Girerd B et al. Absence of influence of gender and BMPR2 mutation type on clinical phenotypes of pulmonary arterial hypertension. Respir Res. 2010 Jun 10;11:73. Koehler R et al. Low frequency of BMPR2 mutations in a German cohort of patients with sporadic idiopathic pulmonary arterial hypertension. J Med Genet. 2004 Dec;41(12):e127. Machado RD et al. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat. 2006 Feb;27(2):121-32. 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 EB 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 Jun;27(6):668-74. Sztrymf B et al. Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. Am J Respir Crit Care Med. 2008 Jun 15;177(12):1377-83. Wang J et al. Functional mutations in 5'UTR of the BMPR2 gene identified in Chinese families with pulmonary arterial hypertension. Pulm Circ. 2016 Mar;6(1):103-8.
Rare Disease Genomics Group, St George's University of London	RCV000461193	SCV000576134	pathogenic	Pulmonary hypertension, primary, 1		no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003700	SCV001162143	pathogenic	Pulmonary arterial hypertension		no assertion criteria provided	research