ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.65A>C (p.Gln22Pro) (rs747437716)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480437 SCV000570929 uncertain significance not provided 2016-07-13 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.65A>C at the cDNA level, p.Gln22Pro (Q22P) at the protein level, and results in the change of a Glutamine to a Proline (CAA>CCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BMPR1A Gln22Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BMPR1A Gln22Pro occurs at a position that is not conserved and is located in the signal peptide region (Howe 2004, UniProt). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict that this variant may lead to the creation of a cryptic splice acceptor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BMPR1A Gln22Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000704484 SCV000833435 uncertain significance Juvenile polyposis syndrome 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces glutamine with proline at codon 22 of the BMPR1A protein (p.Gln22Pro). The glutamine residue is weakly conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is present in population databases (rs747437716, ExAC 0.02%). This variant has not been reported in the literature in individuals with BMPR1A-related disease. ClinVar contains an entry for this variant (Variation ID: 421650). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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