Submissions for variant NM_003722.5(TP63):c.953G>A (p.Arg318His)

dbSNP: rs121908840

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478736	SCV000565627	pathogenic	not provided	2024-12-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate an inhibitory effect of the variant on the wildtype p63 protein, and mouse models for this variant display an ectrodactyly phenotype (PMID: 18626511, 23775923); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as R279H; This variant is associated with the following publications: (PMID: 21652629, 34321610, 23355676, 19353588, 23775923, 20543567, 30566872, 17224651, 18626511, 10535733, 23431748, 11903230)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000548176	SCV000659689	pathogenic	TP63-Related Spectrum Disorders	2022-09-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 318 of the TP63 protein (p.Arg318His). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg318 amino acid residue in TP63. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11462173, 21652629). 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: 18326838, 23775923). 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: 6533). This variant is also known as p.Arg279His. This missense change has been observed in individuals with split hand–split foot malformation (SHFM) or ectrodactyly, ectodermal dysplasia and facial clefts syndrome (EEC syndrome) (PMID: 10535733, 11462173, 12525544, 23355676, 23431748). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency).
3billion, Medical Genetics	RCV000006906	SCV002318671	pathogenic	Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3	2022-03-22	criteria provided, single submitter	clinical testing	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006533, PMID:10535733). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000650760, PMID:19903181,11462173,11462173). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.948>=0.6, 3CNET: 0.993>=0.75). A missense variant is a common mechanism associated with Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
AiLife Diagnostics, AiLife Diagnostics	RCV000478736	SCV002501578	pathogenic	not provided	2021-12-16	criteria provided, single submitter	clinical testing
Division of Medical Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi	RCV000006906	SCV003925547	likely pathogenic	Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3		criteria provided, single submitter	research
OMIM	RCV000006906	SCV000027102	pathogenic	Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3	2003-09-01	no assertion criteria provided	literature only
OMIM	RCV000006907	SCV000027103	pathogenic	Rapp-Hodgkin syndrome	2003-09-01	no assertion criteria provided	literature only