ClinVar Miner

Submissions for variant NM_001204.7(BMPR2):c.1471C>T (p.Arg491Trp) (rs137852746)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genomic Medicine,Kyoto University Graduate School of Medicine RCV000009347 SCV000320702 pathogenic Primary pulmonary hypertension 2016-07-11 no assertion criteria provided clinical testing
GeneDx RCV000493405 SCV000582363 pathogenic not provided 2015-08-27 criteria provided, single submitter clinical testing The R491W variant in the BMPR2 gene has been reported in association with pulmonary hypertension and shown to segregate with the disease phenotype in three families (Deng et al., 2000). Deng et al. (2000) did not identify R491W in 196 control chromosomes and the variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Located in the kinase domain of the BMPR2 gene, R491W results in a non-conservative amino acid substitution of a polar Arginine for a non-polar Tryptophan at a position that is highly conserved across species. A variant in the same residue (R491Q) and in nearby residues (A490V, C496Y) have been reported in HGMD in association with primary pulmonary hypertension (Stenson P et al., 2014), further supporting the functional importance of this residue and region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function; moreover, R491W has been found to be associated with disruption of SMAD pathway signaling (Rudarakanchana et al., 2002; Dewachter et al., 2009).In summary, R491W in the BMPR2 gene is interpreted as a pathogenic variant.
Medical & Molecular Genetics Group,University of Lincoln RCV000009347 SCV000576249 pathogenic Primary pulmonary hypertension no assertion criteria provided literature only
OMIM RCV000009347 SCV000029565 pathogenic Primary pulmonary hypertension 2000-09-01 no assertion criteria provided literature only

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