ClinVar Miner

Submissions for variant NM_003722.5(TP63):c.1028G>A (p.Arg343Gln) (rs121908841)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000276670 SCV000329557 pathogenic not provided 2016-05-02 criteria provided, single submitter clinical testing The R343Q variant in the TP63 gene has been reported previously in the heterozygous state, using alternate nomenclature (R304Q), in association with ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome (Ianakiev et al., 2000; van Bokhoven et al., 2001; Barrow et al., 2002; Dianzani et al., 2003; de Mollerat et al., 2003). The variant, annotated R343Q, was also observed in a female who lacked ectrodactyly, thus diagnosed with Rapp-Hodgkin syndrome and her daughter who reportedly had all of the the cardinal features of EEC (Brueggemann et al., 2016). The R343Q 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. The R343Q 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 across species and within the DNA- binding domain, which is a known mutational hotspot (Ianakiev et al., 2000; van Bokhoven et al., 2001; de Mollerat et al., 2003). In silico analysis predicts this variant is probably damaging to the protein structure/function. Different amino acid changes affecting the same residue (R343W, R343P) and missense variants in nearby residues (C345R, C345Y, A346D, A346G, C347S, C347Y) 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. In summary, we interpret R343Q as a pathogenic variant.
Invitae RCV000655484 SCV000777414 pathogenic TP63-Related Spectrum Disorders 2017-10-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 343 of the TP63 protein (p.Arg343Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome (PMID: 10839977, 12525544, 26882220). It has also been reported in an individual affected with acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome (PMID: 27028492), and an individual affected with Rapp-Hodgkin syndrome (PMID: 26882220).  This variant has also been reported as p.Arg304Gln. ClinVar contains an entry for this variant (Variation ID: 6534). 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: "Benign"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg343Trp, also reported as p.Arg304Trp) has been determined to be pathogenic (PMID: 21652629, 19353588, 10535733, 23355676, 12525544, 20180707, 24734328). This suggests that the arginine residue is critical for TP63 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000006908 SCV000027104 pathogenic Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 2000-07-01 no assertion criteria provided literature only

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