ClinVar Miner

Submissions for variant NM_003239.4(TGFB3):c.898C>T (p.Arg300Trp) (rs796051885)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000332014 SCV000330111 pathogenic not provided 2019-01-21 criteria provided, single submitter clinical testing The R300W pathogenic variant in the TGFB3 gene has been reported previously in four unrelated families with syndromic thoracic aortic aneurysm; the R300W variant segregated with the disease in each family (Bertoli-Avella et al., 2015). The R300W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R300W variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. The R300W variant affects the last amino acid of the latency-associated peptide (LAP) domain, which disrupts the final residue of the recognition motif of a protease cleavage site (Bertoli-Avella et al., 2015). In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (R300G, R300Q) have been reported in individuals with Loeys-Dietz syndrome-5 (Matyas et al., 2014; Kuechler et al., 2015), supporting the functional importance of this residue. Kuechler et al. (2015) postulate that R300 may be a mutational hotspot and pathogenic variants at this residue may lead to increased TGF-beta signaling. We interpret R300W as a pathogenic variant
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000332014 SCV000511089 pathogenic not provided 2016-11-10 criteria provided, single submitter clinical testing
Invitae RCV000525772 SCV000659003 pathogenic Loeys-Dietz syndrome 4 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 300 of the TGFB3 protein (p.Arg300Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (rs796051885, ExAC no frequency). This variant has been reported in four individuals and families affected with syndromic aortic aneurysms (PMID: 25835445). ClinVar contains an entry for this variant (Variation ID: 203490). An additional missense substitution at this codon (p.Arg300Gly) has been shown to segregate with syndromic aortic aneurysms (PMID: 26184463), and a second additional substitution (p.Arg300Gln) was observed de novo in a similarly affected individual (PMID: 24798638). This suggests that the arginine residue is critical for TGFB3 protein function. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000621083 SCV000739712 pathogenic Cardiovascular phenotype 2017-07-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position,Structural Evidence
Blueprint Genetics RCV000332014 SCV000927790 likely pathogenic not provided 2018-07-13 criteria provided, single submitter clinical testing
OMIM RCV000185630 SCV000238545 pathogenic Loeys-Dietz syndrome 5 2015-04-07 no assertion criteria provided literature only

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