ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.1069G>A (p.Ala357Thr) (rs201509164)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000461013 SCV000552850 uncertain significance Juvenile polyposis syndrome 2018-03-07 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 357 of the BMPR1A protein (p.Ala357Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with BMPR1A-related disease. ClinVar contains an entry for this variant (Variation ID: 411619). 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 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 RCV000478306 SCV000565776 uncertain significance not provided 2017-01-10 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.1069G>A at the cDNA level, p.Ala357Thr (A357T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in an astrocytoma and a breast carcinoma (Kan 2010, Shankar 2016). BMPR1A Ala357Thr 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 Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BMPR1A Ala357Thr occurs at a position that is conserved across species and is located in the Cysteine-rich domain of the MH1 domain (Howe 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BMPR1A Ala357Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000567914 SCV000668287 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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