ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.368C>T (p.Pro123Leu) (rs878854713)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493898 SCV000582315 uncertain significance not provided 2017-12-11 criteria provided, single submitter clinical testing The P123L variant has not beenpublished as pathogenic or been reported as benign to our knowledge. However, it has been reported as a variant ofuncertain significance in ClinVar by one other clinical laboratory (SCV000288619.2; Landrum et al., 2016). Thisvariant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015;Exome Variant Server). The P123L variant is a semi-conservative amino acid substitution, which may impactsecondary protein structure as these residues differ in some properties. Moreover, this substitution occurs at a positionthat is conserved across species, and in silico analysis predicts this variant is probably damaging to the proteinstructure/function. Nonetheless, this variant lacks observation in a significant number of affected individuals,segregation data, and functional evidence, which would further clarify its pathogenicity.
Invitae RCV000226439 SCV000288619 uncertain significance Thoracic aortic aneurysm and aortic dissection 2016-05-26 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 123 of the TGFBR1 protein (p.Pro123Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TGFBR1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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