Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001810972 | SCV001477872 | pathogenic | not provided | 2020-02-02 | criteria provided, single submitter | clinical testing | The BMPR2 c.38G>A; p.Trp13Ter variant (rs1085307151) is reported in the literature in individuals affected with pulmonary arterial hypertension (Chida 2012, Machado 2015). This variant is also reported in ClinVar (Variation ID: 425682), but 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 (NMD). Additionally, another variant at this codon (c.39G>A; p.Trp13Ter) has been reported in a family with pulmonary arterial hypertension and is considered pathogenic (Hamid 2010). In vitro functional analyses of the c.39G>A variant show that while the transcript does not undergo NMD, the variant results in a truncated protein missing the ligand binding domain and part of the transmembrane domain (Hamid 2010). Based on available information, the c.38G>A; p.Trp13Ter variant is considered to be pathogenic. References: Chida A et al. Outcomes of childhood pulmonary arterial hypertension in BMPR2 and ALK1 mutation carriers. Am J Cardiol. 2012 Aug 15;110(4):586-93. Hamid R et al. Transcripts from a novel BMPR2 termination mutation escape nonsense mediated decay by downstream translation re-initiation: implications for treating pulmonary hypertension. Clin Genet. 2010 Mar;77(3):280-6. Machado RD et al. Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects. Hum Mutat. 2015 Dec;36(12):1113-27. |
| Labcorp Genetics |
RCV001856887 | SCV002235826 | pathogenic | Primary pulmonary hypertension | 2021-08-12 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Trp13*) 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 (ExAC no frequency). This premature translational stop signal has been observed in individuals with pulmonary arterial hypertension (PMID: 22632830, 26387786). ClinVar contains an entry for this variant (Variation ID: 425682). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. |
| Rare Disease Genomics Group, |
RCV000488831 | SCV000575954 | pathogenic | Pulmonary hypertension, primary, 1 | no assertion criteria provided | literature only |