Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Broad Center for Mendelian Genomics, |
RCV003226095 | SCV003922233 | likely pathogenic | Coffin-Siris syndrome 1 | 2023-05-02 | criteria provided, single submitter | curation | The heterozygous p.Leu1806ValfsTer9 variant in ARID1B was identified by our study in one individual with partial agenesis of the corpus callosum. Trio exome analysis showed this variant to be de novo. The p.Leu1806ValfsTer9 variant in ARID1B has not been previously reported in individuals with Coffin-Siris syndrome 1. 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 1806 and leads to a premature termination codon 9 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. Heterozygous loss of function of the ARID1B gene is an established disease mechanism in autosomal dominant Coffin-Siris syndrome 1. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant Coffin-Siris syndrome 1. ACMG/AMP Criteria applied: PVS1_Strong, PS2_Supporting, PM2_Supporting (Richards 2015). |