ClinVar Miner

Submissions for variant NM_003722.5(TP63):c.1048A>G (p.Arg350Gly) (rs1057517985)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413411 SCV000491280 likely pathogenic not provided 2016-08-16 criteria provided, single submitter clinical testing A novel de novo R350G likely pathogenic variant was identified in the TP63 gene. R350G has been reported previously as R311G using alternate nomenclature in association with EEC (ectrodactyly, ectodermal dysplasia, clefting) (Clements et al., 2010), and its presence is consistent with the diagnosis in this fetus. The R350G variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R350G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (C345R/Y, A346G/D, C347S/Y, P348S, G349E, D351H/N/G/E, R352G, A354E) have been reported in the Human Gene Mutation Database in association with Ectrodactyly-ED-Clefting (EEC) and related syndromes (Stenson et al., 2014), supporting the functional importance of this region of the protein. This substitution occurs at a position that is conserved across species within the DNA-binding region, where most pathogenic variants that cause EEC are located (Browne et al., 2011). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

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