ClinVar Miner

Submissions for variant NM_003239.4(TGFB3):c.77C>G (p.Thr26Ser) (rs771543236)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000428232 SCV000535302 uncertain significance not provided 2017-01-12 criteria provided, single submitter clinical testing The T26S variant in the TGFB3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The T26S 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 T26S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T26S as a variant of uncertain significance, which may be related to the reported arrhythmia in this individual.
Invitae RCV000704957 SCV000833932 uncertain significance Loeys-Dietz syndrome 4 2018-02-09 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 26 of the TGFB3 protein (p.Thr26Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs771543236, ExAC 0.001%). This variant has not been reported in the literature in individuals with TGFB3-related disease. ClinVar contains an entry for this variant (Variation ID: 392089). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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