Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002231276 | SCV000629977 | uncertain significance | Primary pulmonary hypertension | 2017-05-03 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with arginine at codon 426 of the BMPR2 protein (p.Gly426Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 9 of the BMPR2 coding sequence, which is part of the consensus splice site for this exon. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BMPR2-related disease. However, a different variant affecting the same nucleotide and resulting in the same amino acid change (c.1276G>C (p.Gly426Arg)) has been reported in the literature in an individual affected with heritable pulmonary arterial hypertension (PMID: 26387786). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. |