Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000394306 | SCV000329554 | pathogenic | not provided | 2016-08-26 | criteria provided, single submitter | clinical testing | The R243W variant has been reported previously in association with TP63-related disorders (for examples, see Celli et al., 1999; Kosaki et al. 2008; Avitan-Hersh et al. 2010). In vitro functional studies demonstrated that this variant results in complete loss of transactivation function, and prevents transcription of Hdm2, p21, Shh, and VDR proteins (Khokhar et al., 2008; Kirschner et al. 2010; Monti et al. 2013). The R243W 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. The R243W 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. This substitution occurs at a position that is conserved across species, and is located within the DNA binding domain (van Vokhoven et al., 2001). Missense variants in this residue (R243Q, R243L) and in nearby residues (V241M, H247Y, H247D, H247R) 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. Based on currently available evidence, we consider R243W to be pathogenic. |
| EGL Genetic Diagnostics, |
RCV000394306 | SCV000708583 | pathogenic | not provided | 2017-05-23 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000812084 | SCV000952388 | pathogenic | TP63-Related Spectrum Disorders | 2018-09-07 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with tryptophan at codon 243 of the TP63 protein (p.Arg243Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals and families affected with a TP63-related disease, including ectrodactyly-ectodermal dysplasia-cleft (EEC) syndrome and ADULT syndrome, in some of whom it was found de novo (PMID: 10535733, 23355676, 21078104, 18792980, 22607287). This variant is also known as p.Arg204Trp in the literature. ClinVar contains an entry for this variant (Variation ID: 6527). Experimental studies have shown that this missense variant results in a protein that lacks transactivation ability and is able to inhibit the function of the wild type protein (PMID: 18626511, 23355676, 23463580). This variant disrupts the p.Arg243 amino acid residue in TP63. Other variants that disrupt this residue have been observed in affected individuals (PMID: 28293528, 29620206, 12525544), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000006900 | SCV000027096 | pathogenic | Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 | 2008-10-01 | no assertion criteria provided | literature only |