ClinVar Miner

Submissions for variant NM_003722.5(TP63):c.1655T>G (p.Phe552Cys) (rs886039443)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255981 SCV000321976 likely pathogenic not provided 2016-07-22 criteria provided, single submitter clinical testing p.F552C has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. F552C 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. This substitution occurs at a position within the SAM domain that is conserved across species; 82% of pathogenic variants associated with AEC syndrome are estimated to occur in the SAM domain (Sutton et al., 2015). In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, variants in the F552 position are predicted to adversely affect the overall structure and stability of the protein (Sirico et al., 2014). Missense variants in the same residue (F552S) and in nearby residues (I549T, L553V/S/F, G557V) have been reported in the Human Gene Mutation Database in association with TP63-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

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