ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.987A>C (p.Arg329Ser) (rs753521037)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588080 SCV000293825 uncertain significance not provided 2018-10-15 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.987A>C at the cDNA level, p.Arg329Ser (R329S) at the protein level, and results in the change of an Arginine to a Serine (AGA>AGC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BMPR1A Arg329Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the protein kinase domain (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BMPR1A Arg329Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000465582 SCV000552871 uncertain significance Juvenile polyposis syndrome 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 329 of the BMPR1A protein (p.Arg329Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs753521037, ExAC 0.006%) but has not been reported in the literature in individuals with a BMPR1A-related disease. ClinVar contains an entry for this variant (Variation ID: 246321). 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 variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000561962 SCV000668309 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (benign)
Color RCV000561962 SCV000682926 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588080 SCV000698329 uncertain significance not provided 2017-01-19 criteria provided, single submitter clinical testing Variant summary: The BMPR1A c.987A>C (p.Arg329Ser) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121360 control chromosomes at a frequency of 0.0000082, which is approximately 4 times the estimated maximal expected allele frequency of a pathogenic BMPR1A variant (0.000002). In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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