Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Broad Center for Mendelian Genomics, |
RCV002789981 | SCV003761268 | likely pathogenic | Intellectual disability, autosomal dominant 22 | 2023-01-25 | criteria provided, single submitter | curation | The heterozygous p.Ile103LeufsTer5 variant in ZBTB18 was identified by our study in one individual with partial agenesis of the corpus callosum and global developmental delay. Trio exome analysis showed this variant to be de novo. The p.Ile103LeufsTer5 variant in ZBTB18 has not been previously reported in individuals with autosomal dominant intellectual disability 22. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 103 and leads to a premature termination codon 5 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. However, the variant is predicted to remove >80% of the normal protein sequence and is therefore likely to lead to loss of function. Heterozygous loss of function of the ZBTB18 gene is strongly associated to autosomal dominant intellectual disability 22. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant intellectual disability. ACMG/AMP Criteria applied: PVS1_Strong, PS2_Supporting, PM2_Supporting (Richards 2015). |