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

dbSNP: rs886039443

Total submissions: 2

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.
Invitae	RCV001298548	SCV001487607	uncertain significance	TP63-Related Spectrum Disorders	2020-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine with cysteine at codon 552 of the TP63 protein (p.Phe552Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. 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. This variant disrupts the p.Phe552 amino acid residue in TP63. Other variant(s) that disrupt this residue have been observed in individuals with TP63-related conditions (PMID: 19840326, 20491771), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with ankyloblepharon-ectodermal defects-cleft lip/palate (Invitae). ClinVar contains an entry for this variant (Variation ID: 265277). This variant is not present in population databases (ExAC no frequency).