ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.751G>T (p.Gly251Cys) (rs750513716)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000545911 SCV000632733 uncertain significance Juvenile polyposis syndrome 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 251 of the BMPR1A protein (p.Gly251Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. 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: 460511). 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.
Ambry Genetics RCV000569001 SCV000673002 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000569001 SCV000682915 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587600 SCV000698326 uncertain significance not provided 2016-07-11 criteria provided, single submitter clinical testing Variant summary: The BMPR1A c.751G>T (p.Gly251Cys) variant causes a missense change involving a conserved nucleotide with 5/5 in silico tools predicting a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC with an allele frequency of 6/120956 (1/20161), which does exceed the estimated maximal expected allele frequency for a pathogenic BMPR1A variant of 1/500000 (0.000002). However, this observation needs to be cautiously considered because the database does indicate low coverage at the cite, in addition, the cohort could harbor individuals that have a BMPR1A phenotype. The variant of interest, to our knowledge, has not been reported in affected individuals via publications and/or reputable databases/clinical laboratories. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a "VUS-possibly benign," until additional information becomes available.

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