ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.1425G>T (p.Trp475Cys) (rs767589799)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000490239 SCV000577693 likely pathogenic not provided 2015-07-10 criteria provided, single submitter clinical testing The W475C variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. However, it has been observed in one other individual who had DNA-based testing at GeneDx due to a possible connective tissue disorder. The W475C 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. Additionally, the W475C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and this substitution occurs at a position that is conserved across species. Furthermore, a missense variants in a nearby residue (N478S) has been reported in the Human Gene Mutation Database in association with Loeys-Dietz syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Finally, in silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded

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