ClinVar Miner

Submissions for variant NM_003722.5(TP63):c.953G>A (p.Arg318His) (rs121908840)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478736 SCV000565627 pathogenic not provided 2017-11-09 criteria provided, single submitter clinical testing The R318H variant in the TP63 gene has been reported previously, as R279H due to the use of alternate nomenclature, in a mother and two affected children with EEC syndrome; this variant was absent in two unaffected children (Celli et al., 1999). The R318H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R318H variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In vitro assays demonstrate that R318H acts in a dominant-negative manner to inhibit wildtype TAp63γ-mediated transactivation (Khokhar et al., 2008). We interpret R318H as a pathogenic variant.
Invitae RCV000548176 SCV000659689 pathogenic TP63-Related Spectrum Disorders 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 318 of the TP63 protein (p.Arg318His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with ectrodactyly, ectodermal dysplasia and facial clefts syndrome (EEC syndrome) in a family with 3 affected individuals (PMID: 10535733), In addition, this variant has been observed in multiple individuals wtih EEC syndrome (PMID: 23431748, 23355676, 12525544) and in individuals with split hand–split foot malformation (SHFM) (PMID: 11462173). ClinVar contains an entry for this variant (Variation ID: 6533). This variant is also known as p.Arg279His. Experimental studies have shown that this missense change results in lack of transactivation ability for some TP63 target genes [PMID: 19353588, 20543567, 21652629, 18626511) and a knock-in mouse model for this variant recapitulates features observed in human EEC syndrome including limb defects (PMID: 23775923, 18326838). Variants that disrupt the p.Arg318 (also known as p.Arg279) amino acid residue in TP63 have been observed in affected individuals (PMID:  11462173, 21652629). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
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 ectodermal dysplasia syndrome 2003-09-01 no assertion criteria provided literature only

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