ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.233C>T (p.Thr78Ile) (rs1064793490)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478119 SCV000566248 uncertain significance not provided 2015-04-14 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.233C>T at the cDNA level, p.Thr78Ile (T78I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). This variant was observed in multiple individuals with juvenile polyposis syndrome (Howe 2004, Kurland 2007, Calva-Cerqueira 2009, Huang 2011). In addition, in vitro analysis of this variant demonstrated protein expression levels similar to wild type, but deficient signaling and intracellular localization (Howe 2013). BMPR1A Thr78Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BMPR1A Thr78Ile occurs at a position that is conserved across species and is located in the MH1 domain (Howe 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BMPR1A Thr78Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000794170 SCV000933561 uncertain significance Juvenile polyposis syndrome 2018-08-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 78 of the BMPR1A protein (p.Thr78Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with juvenile polyposis (PMID: 15235019). ClinVar contains an entry for this variant (Variation ID: 418873). Experimental studies have shown that this missense change affects cellular localization of the BMPR1A protein (PMID: 23433720). 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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