ClinVar

Description

The c.3211T>C (p.S1071P) alteration is located in exon 10 (coding exon 9) of the ZEB2 gene. This alteration results from a T to C substitution at nucleotide position 3211, causing the serine (S) at amino acid position 1071 to be replaced by a proline (P). Based on data from the Genome Aggregation Database (gnomAD), the ZEB2 c.3211T>C alteration was not observed, with coverage at this position. This alteration has been reported in a patient with moderate intellectual disability and the facial gestalt suggestive of Mowat Wilson syndrome. The patient was reported to have seizures, onset at 2 years 9 months, but no other congenital anomalies and had a normal brain MRI (Ghoumid, 2013). Another patient with this alteration was reported to have mild intellectual disability, epilepsy, language delay, a happy demeanor, constipation and mild dysmorphic features (Wenger, 2014). This amino acid position is highly conserved in available vertebrate species. The p.S1071P amino acid is located within the highly conserved C-zinc-finger (C-ZF) domain of ZEB2 (Ghoumid, 2013). The ZF domains function to bind target-promoter DNA needed for transactivation of the protein. In vitro functional analysis on the E-cadherin promoter showed that the integrity of ZEB2 C-ZF is necessary for proper DNA-binding and transactivation activities of the protein (Ghoumid, 2013). The zebrafish in vivo model was used to show that human ZEB2 mRNAs carrying the p.S1071P alteration could variably rescue sip1b morphant embryos and suggested that ZEB2 function was not restricted to repression of the E-cadherin (Ghoumid, 2013). The in silico prediction for the p.S1071P alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.