Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000551822 | SCV000659686 | uncertain significance | TP63-Related Spectrum Disorders | 2017-07-10 | criteria provided, single submitter | clinical testing | 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 falls in the last intron of the TP63 gene, and may disrupt splicing of the final exon. A number of variants that truncate the final exon have been reported in individuals affected with TP63-related disorders (PMID: 11462173, 16691622, 19676060). Experimental studies have shown that there is an inhibitory domain at the end of the protein that represses TP63 transcriptional activity, and that deletion of this region results in aberrantly increased transcription (PMID: 12446779, 15539951, 21652629). However, the effect of this particular variant on TP63 RNA splicing and protein function is currently unknown. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with TP63-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 13 of the TP63 gene. It does not directly change the encoded amino acid sequence of the TP63 protein, but it affects a nucleotide within the consensus splice site of the intron. |