ClinVar Miner

Submissions for variant NM_001204.7(BMPR2):c.1128+1G>A (rs863223420)

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Total submissions: 4
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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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000197596 SCV000335388 pathogenic not provided 2015-09-15 criteria provided, single submitter clinical testing
Invitae RCV000323481 SCV000813966 pathogenic Primary pulmonary hypertension 2018-05-18 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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with pulmonary arterial hypertension (PAH) (PMID: 16429395). ClinVar contains an entry for this variant (Variation ID: 212811). A different variant affecting this nucleotide (c.1128+1G>T) has been determined to be pathogenic (PMID: 12821254). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be 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). For these reasons, this variant has been classified as Pathogenic.
Medical & Molecular Genetics Group,University of Lincoln RCV000323481 SCV000576169 pathogenic Primary pulmonary hypertension no assertion criteria provided literature only

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