ClinVar Miner

Submissions for variant NM_003239.4(TGFB3):c.872C>T (p.Pro291Leu) (rs145121701)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482159 SCV000573474 uncertain significance not provided 2017-09-29 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TGFB3 gene. The P291L variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P291L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000473364 SCV000550895 uncertain significance Loeys-Dietz syndrome 4 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 291 of the TGFB3 protein (p.Pro291Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs145121701, ExAC 0.02%) but has not been reported in the literature in individuals with a TGFB3-related disease. ClinVar contains an entry for this variant (Variation ID: 410274). 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.

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