ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.253A>G (p.Ile85Val) (rs374739820)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130327 SCV000185177 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-30 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000206721 SCV000260495 uncertain significance Juvenile polyposis syndrome 2018-05-03 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 85 of the BMPR1A protein (p.Ile85Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs374739820, ExAC 0.002%). This variant has not been reported in the literature in individuals with BMPR1A-related disease. ClinVar contains an entry for this variant (Variation ID: 141710). 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.
GeneDx RCV000487158 SCV000572674 uncertain significance not provided 2018-04-04 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.253A>G at the cDNA level, p.Ile85Val (I85V) at the protein level, and results in the change of an Isoleucine to a Valine (ATC>GTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BMPR1A Ile85Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the extracellular domain and a cysteine-rich region of the MH1 domain (Howe 2004, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BMPR1A Ile85Val is pathogenic or benign. We consider it to be a variant of uncertain significance.

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