ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.1432C>T (p.Arg478Cys) (rs372178531)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236117 SCV000293992 uncertain significance not provided 2018-03-08 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.1432C>T at the cDNA level, p.Arg478Cys (R478C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant was observed in a patient undergoing multigene panel testing for a history of a Lynch syndrome-related cancer and/or polyps (Yurgelun 2015). BMPR1A Arg478Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the protein kinase domain (Howe 2004). Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect.? Based on currently available evidence, it is unclear whether BMPR1A Arg478Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000468095 SCV000552877 uncertain significance Juvenile polyposis syndrome 2017-09-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 478 of the BMPR1A protein (p.Arg478Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs372178531, ExAC 0.01%). This variant has not been reported in the literature in individuals with BMPR1A-related disease. ClinVar contains an entry for this variant (Variation ID: 246435). 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.
Ambry Genetics RCV000561021 SCV000668326 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000561021 SCV000682868 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-13 criteria provided, single submitter clinical testing
Counsyl RCV000468095 SCV000785449 uncertain significance Juvenile polyposis syndrome 2017-08-11 criteria provided, single submitter clinical testing

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