Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000273960 | SCV000330788 | pathogenic | not provided | 2018-03-22 | criteria provided, single submitter | clinical testing | Although the c.1128+1 G>C variant has not been reported as a pathogenic variant or as a benign variant to our knowledge, it destroys the canonical splice donor site in intron 8 and is predicted to cause abnormal gene splicing. This variant 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 variants in the BMPR2 gene have been reported in HGMD in association with PAH (Stenson et al., 2014), including a pathogenic splice site variant at the same nucleotide position (c.1128+1 G>T), supporting the functional importance of this nucleotide. Furthermore, the c.1128+1 G>C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.1128+1 G>C in the BMPR2 gene is interpreted as a pathogenic variant. |
| Invitae | RCV002229735 | SCV000943337 | pathogenic | Primary pulmonary hypertension | 2018-08-30 | 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 and likely results in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BMPR2 are known to be pathogenic (PMID: 16429395). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individuals affected with pulmonary hypertension (PMID: 12821254, 16429395, 29650961, Invitae). ClinVar contains an entry for this variant (Variation ID: 280837). This variant is not present in population databases (ExAC no frequency). |
| Wendy Chung Laboratory, |
RCV001823884 | SCV002073625 | not provided | Pulmonary arterial hypertension; Idiopathic and/or familial pulmonary arterial hypertension | no assertion provided | literature only |