ClinVar Miner

Submissions for variant NM_003722.5(TP63):c.740A>G (p.His247Arg) (rs864621968)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia,Universidade Católica de Brasília RCV000206266 SCV000223904 pathogenic Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 2015-04-01 criteria provided, single submitter research
GeneDx RCV000312203 SCV000329555 pathogenic not provided 2018-06-04 criteria provided, single submitter clinical testing The H247R variant has been published as a pathogenic variant in association with Ectrodactyly-Ectodermal dysplasia-Clefting (EEC) syndrome (Clements et al., 2010). The H247R variant has also been confirmed de novo in an affected individual tested at GeneDx. The H247R variant is not observed in large population cohorts (Lek et al., 2016). The H247R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in this residue (H247D, H247Y, H247Q) and in nearby residues (K242E, R243L, R243W, R243Q) have been reported in the Human Gene Mutation Database in association with EEC (Stenson et al., 2014). In summary, this variant is pathogenic.
Invitae RCV000821003 SCV000961742 pathogenic TP63-Related Spectrum Disorders 2018-09-18 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 247 of the TP63 protein (p.His247Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with ectrodactyly–ectodermal dysplasia–cleft lip ⁄ palate (EEC) syndrome (PMID: 19903181, 26380986). ClinVar contains an entry for this variant (Variation ID: 208163). This variant has also been reported as c.623A>G, p.His208Arg. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Two different missense substitution at this codon (p.His247Tyr and p.His247Asp) have been reported in individuals affected with EEC syndrome (PMID: 16691622, 19663851). This suggests that the histidine residue is critical for TP63 protein function. In the literature, the p.His247Tyr variant and the p.His247Asp variant are referred to as p.His208Tyr and p.His208Asp, respectively. For these reasons, this variant has been classified as Pathogenic.

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