Submissions for variant NM_001204.7(BMPR2):c.1128+1G>A

dbSNP: rs863223420

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197596	SCV000249643	pathogenic	not provided	2015-04-22	criteria provided, single submitter	clinical testing	c.1128+1 G>A: IVS8+1 G>A in exon 8 of the BMPR2 gene (NM_001204.6). The c.1128+1 G>A mutation has been reported in at least one individual with idiopathic PAH (Machado et al., 2006). Additionally, a substitution at this same position (c.1128+1 G>T) has been reported in at least three individuals with PAH and was absent from 60 healthy control individuals (Rinderman et al., 2003; Cogan et al., 2006; Machado et al., 2006). This mutation destroys the canonical splice donor site in intron 8 and is predicted to cause abnormal gene splicing. The mutation is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site mutations in the BMPR2 gene have been reported in association with PAH. In summary, c.1128+1 G>A in the BMPR2 gene is interpreted as a disease-causing mutation. This variant was found in BMPR2,PAH-ARRHYTHMIA
Eurofins Ntd Llc (ga)	RCV000197596	SCV000335388	pathogenic	not provided	2015-09-15	criteria provided, single submitter	clinical testing
Invitae	RCV002229023	SCV000813966	pathogenic	Primary pulmonary hypertension	2023-11-22	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 8 of the BMPR2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BMPR2 are known to be pathogenic (PMID: 16429395). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with pulmonary arterial hypertension (PMID: 16429395). ClinVar contains an entry for this variant (Variation ID: 212811). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000197596	SCV001472178	pathogenic	not provided	2019-09-12	criteria provided, single submitter	clinical testing	The BMPR2 c.1128+1G>A variant (rs863223420) is reported in the literature in individuals affected with idiopathic pulmonary arterial hypertension (Machado 2006, Wang 2019), and a similar variant with a different nucleotide change, c.1128+1G>T, was also reported in two affected families (Cogan 2006, Koelher 2004, Pfarr 2011, Rindermann 2003). The c.1128+1G>A variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 212811), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 8. Functional assays show that the c.1128+1G>T variant results in a stable transcript with an in-frame skipping of exons 8 and 9 (Cogan 2006). Based on available information, the c.1128+1G>A variant is considered to be pathogenic. REFERENCES Cogan DJ et al. High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006 Sep 1;174(5):590-8. 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-b 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. Rindermann M et al. Primary pulmonary hypertension may be a heterogeneous disease with a second locus on chromosome 2q31. J Am Coll Cardiol. 2003 Jun 18;41(12):2237-44. Wang XJ et al. Germline BMP9 mutation causes idiopathic pulmonary arterial hypertension. Eur Respir J. 2019 Mar 14;53(3). pii: 1801609.
Rare Disease Genomics Group, St George's University of London	RCV000323481	SCV000576169	pathogenic	Pulmonary hypertension, primary, 1		no assertion criteria provided	literature only
Wendy Chung Laboratory, Columbia University Medical Center	RCV001823877	SCV002073624	not provided	Pulmonary arterial hypertension; Idiopathic and/or familial pulmonary arterial hypertension		no assertion provided	literature only