Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000429171 | SCV000524419 | likely pathogenic | not provided | 2016-03-04 | criteria provided, single submitter | clinical testing | The G173R variant in the TP63 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G173R 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 G173R variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Other missense variants in the same residue (G173D, G173V) 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. The G173R variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. |
| Invitae | RCV000695697 | SCV000824212 | pathogenic | TP63-Related Spectrum Disorders | 2019-08-20 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly173 amino acid residue in TP63. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21990121, 23463580). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to segregate with TP63-related disorders in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 383835). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 173 of the TP63 protein (p.Gly173Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. |