Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| New York Genome Center | RCV001420590 | SCV001622905 | uncertain significance | Developmental and epileptic encephalopathy, 67 | 2020-05-19 | criteria provided, single submitter | clinical testing | The de novo c.3133C>T (p.Pro1045Ser) variant identified in the CUX2 gene substitutes a very well conserved Proline for Serine at amino acid 1045/1487 (coding exon 19/22). This variant is absent from gnomAD(v3.0) suggesting it is not a common benign variant in the populations represented in this database. In silico algorithms do not agree on the effect of this variant, as it is predicted Deleterious (Provean; -6.12), Damaging (SIFT; score:0.003), and Benign (REVEL; score:0.1679) to the function of the canonical transcript. This variant is absent from ClinVar and to our current knowledge has not been reported in affected individuals in the literature. The p.Pro1045 residue is within the CUT3 DNA Binding domain of CUX2 (residues 1038-1125; UniProtKB:O14529), however to our current knowledge no affected individuals have been identified in the literature with missense variants in this domain. To date only a single recurrent missense variant, p.Glu590Lys, within the first DNA binding domain of CUX2 has been identified in individuals with CUX2 associated epileptic encephalopathy [PMID:29795476; PMID:29630738], and functional studies have not been performed in affected individuals to determine the molecular pathogenesis of this specific variant. Given this, and the uncertainty regarding additional missense variants in the CUX2 gene, the de novo c.3133C>T (p.Pro1045Ser) variant is reported here as a Variant of Uncertain Significance. |