ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.377G>T (p.Arg126Leu) (rs864622549)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206669 SCV000261083 uncertain significance Juvenile polyposis syndrome 2016-01-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 126 of the BMPR1A protein (p.Arg126Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BMPR1A-related disease. 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. In summary, this is a novel missense change that is not predicted to affect protein function or cause disease. However, the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000236577 SCV000293655 uncertain significance not provided 2016-08-22 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.377G>T at the cDNA level, p.Arg126Leu (R126L) at the protein level, and results in the change of an Arginine to a Leucine (CGG>CTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BMPR1A Arg126Leu 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 Arginine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BMPR1A Arg126Leu occurs at a position that is conserved in mammals and is located in the MH1 domain (Howe 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BMPR1A Arg126Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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