Submissions for variant NM_003722.5(TP63):c.727C>T (p.Arg243Trp)

gnomAD frequency: 0.00001  dbSNP: rs121908835

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000394306	SCV000329554	pathogenic	not provided	2022-06-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate variant causes a 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); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10535733, 31502745, 29620206, 29802835, 29339502, 18626511, 21652629, 20543567, 18792980, 23355676, 23463580, 21078104, 22607287, 32476291, 30088137, 32881366, 28293528, 31333354, 34246755, 17224651, Savukyne_2022)
Eurofins Ntd Llc (ga)	RCV000394306	SCV000708583	pathogenic	not provided	2017-05-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812084	SCV000952388	pathogenic	TP63-Related Spectrum Disorders	2023-02-25	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) 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, 18792980, 21078104, 22607287, 23355676). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg243 amino acid residue in TP63. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12525544, 28293528, 29620206). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TP63 function (PMID: 18626511, 23355676, 23463580). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP63 protein function. ClinVar contains an entry for this variant (Variation ID: 6527). This variant is also known as p.Arg204Trp. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 243 of the TP63 protein (p.Arg243Trp).
CeGaT Center for Human Genetics Tuebingen	RCV000394306	SCV001746791	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	TP63: PS2, PM2, PM5, PS4:Moderate, PP3, PP4, PS3:Supporting
3billion, Medical Genetics	RCV002283440	SCV002572774	pathogenic	Rapp-Hodgkin syndrome	2022-09-01	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: 0.95; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006527). A different missense change at the same codon (p.Arg243Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006528). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000006900	SCV005086132	pathogenic	Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Dominant negative is associated with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (MIM#604292), limb-mammary syndrome (MIM#603543) and ankyloblepharon‑ectodermal defects‑cleft lip/palate syndrome. While gain of function is associated with ADULT syndrome (MIM#103285), and loss of function is likely associated with orofacial cleft 8 (MIM#618149) (PMIDs: 20556892, 32476291, 29620206). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. TP63-related conditions are known to have wide phenotypic variability even among members of the same family (PMIDs: 20556892, 32476291, 29620206). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated P53 DNA-binding domain (DECIPHER). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Arg243Gln) has been classified as pathogenic by several clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and has been observed in individuals with EEC3, SHFM, and ADULT syndrome in the literature (PMIDs: 32476291, 20556892). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005025017	SCV005660623	pathogenic	ADULT syndrome; Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome; Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3; Limb-mammary syndrome; Rapp-Hodgkin syndrome; Split hand-foot malformation 4; Orofacial cleft 8; Premature ovarian failure 21	2024-01-31	criteria provided, single submitter	clinical testing
OMIM	RCV000006900	SCV000027096	pathogenic	Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3	2008-10-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000394306	SCV001744922	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000394306	SCV001957172	pathogenic	not provided		no assertion criteria provided	clinical testing