ClinVar Miner

Submissions for variant NM_003722.5(TP63):c.1727T>C (p.Ile576Thr) (rs1057517841)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413999 SCV000490860 pathogenic not provided 2015-08-25 criteria provided, single submitter clinical testing The I576T missense variant in the TP63 gene has been reported previously in association with Hay-Wells syndrome using alternate nomenclature (McGrath et al., 2001; Tomkova et al., 2010; Alessandro et al., 2013). This variant is present in the hydrophobic core of the SAM domain, and studies have shown that replacing the non-polar Isoleucine residue with a polar Threonine residue destabilizes the protein and affects its function (Sathyamurthy et al., 2011; Browne et al., 2011). Therefore, we interpret this variant as pathogenic.
Invitae RCV000534217 SCV000659685 pathogenic TP63-Related Spectrum Disorders 2017-08-10 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 576 of the TP63 protein (p.Ile576Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome in a single family (PMID: 20156774). This variant has also been reported in unrelated individuals with AEC syndrome (PMID: 11159940, Invitae). This variant is also known as p.Ile537Thr or p.Ile541Thr.  ClinVar contains an entry for this variant (Variation ID: 372540). Experimental studies have shown that this missense results in increased protein expression and reduced transactivation activity on skin specific promoters (PMID: 21652629). In addition, this variant showed decreased protein stability in experiments to determine crystal structure (PMID: 21615690). For these reasons, this variant has been classified as Pathogenic.

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