Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV002255067 | SCV002526349 | likely pathogenic | not provided | 2021-12-07 | criteria provided, single submitter | clinical testing | Frameshift variant predicted to result in protein truncation, as the last 84 amino acids are replaced with 53 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge |
| Broad Center for Mendelian Genomics, |
RCV002280208 | SCV002568399 | likely pathogenic | Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures | 2022-08-25 | criteria provided, single submitter | curation | The heterozygous p.Leu713fs variant in IRF2BPL was identified in 1 individual with a neurodevelopmental disorder including absent speech, seizure, global developmental delay, dystonia, athetosis, and abnormal social behavior via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Neurodev Study (https://www.neurodevproject.org/). Trio exome analysis showed this variant to be de novo. The p.Leu713fs variant in IRF2BPL has not been previously reported in individuals with a neurodevelopmental disorder and 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 713 and leads to a premature termination codon 54 amino acids downstream. This gene is a single exon gene so frameshift variants are more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. However, this variant is predicted to remove >10% of the normal protein sequence, and is therefore likely to disrupt protein function. Heterozygous loss of function of the IRF2BPL gene is an established disease mechanism in neurodevelopmental disorders. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant neurodevelopmental disorder. ACMG/AMP Criteria applied: PVS1_strong, PS2_moderate, PM2_supporting (Richards 2015). |