Submissions for variant NM_003722.5(TP63):c.1027C>T (p.Arg343Trp)

dbSNP: rs886041251

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000371222	SCV000329556	pathogenic	not provided	2020-11-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate this variant causes the TP63 protein to accumulate in the skin of EEC patients and extends the half-life of the protein. Additionally, the R343W variant protein shows reduced transcriptional activity as compared to wild-type protein (Browne et al., 2011); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27135912, 11462173, 19353588, 20180707, 23355676, 10535733, 21652629, 28400699, 29130604, 30566872, 24734328, 30025988, 30850703)
Invitae	RCV001050126	SCV001214219	pathogenic	TP63-Related Spectrum Disorders	2019-04-17	criteria provided, single submitter	clinical testing	This variant disrupts the p.Arg343 amino acid residue in TP63. Other variant(s) that disrupt this residue have been observed in individuals with TP63-related conditions (PMID: 10839977, 12525544, 26882220), 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. This variant has been reported to affect TP63 protein function (PMID: 19353588, 23355676). This variant has been observed in individuals affected with ectrodactyly, ectodermal dysplasia, cleft lip and palate (EEC) syndrome; in several of these cases, it was observed to be de novo (PMID: 10535733, 20180707, 24734328). This variant is also known as c.910C>T, p.Arg304Trp in the literature. ClinVar contains an entry for this variant (Variation ID: 279913). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 343 of the TP63 protein (p.Arg343Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan.
3billion	RCV003152702	SCV003841956	pathogenic	Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000279913). A different missense change at the same codon (p.Arg343Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006534). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000371222	SCV002034953	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000371222	SCV002037352	pathogenic	not provided		no assertion criteria provided	clinical testing