ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.562C>T (p.Arg188Cys) (rs879254272)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236618 SCV000294033 uncertain significance not provided 2016-03-02 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.562C>T at the cDNA level, p.Arg188Cys (R188C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BMPR1A Arg188Cys 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 Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BMPR1A Arg188Cys occurs at a position that is not conserved and is not located in a known functional 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 Arg188Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000477266 SCV000552898 uncertain significance Juvenile polyposis syndrome 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 188 of the BMPR1A protein (p.Arg188Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BMPR1A-related disease. ClinVar contains an entry for this variant (Variation ID: 246466). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
University of Washington Department of Laboratory Medicine,University of Washington RCV000491978 SCV000579492 likely benign Hereditary cancer-predisposing syndrome 2016-05-17 criteria provided, single submitter clinical testing The BMPR1A p.R188C, c.562 C>T variant did not segregate with colon cancer or polyposis in a single large family. Two individuals with no polyps did not have this BMPR1A variant and the majority of indivduals with multiple polyps or colon cancer did not have this variant. Based on this information, the likelihood that BMPR1A p.R188C is associated associated with polyposis is estimated to be less than one in one hundred.
Ambry Genetics RCV000491978 SCV000668320 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000491978 SCV000688282 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-31 criteria provided, single submitter clinical testing

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