Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Randwick Genomics Laboratory, |
RCV001533455 | SCV001750059 | likely pathogenic | DNA ligase IV deficiency | criteria provided, single submitter | clinical testing | DNA ligase IV deficiency is a rare primary immunodeficiency that is often associated with other systemic features. Common features include primordial growth failure with severe microcephaly and a spectrum of learning difficulties, immune function that ranges from normal to severe combined immunodeficiency, marrow hypoplasia and a predisposition to lymphoid malignancy. Radial ray anomalies and atrophic/ dysplastic kidneys have also been reported in this condition (PMID 32534991). The homozygous LIG4:c.2401_2410del is a deletion of 10bp in exon 2 which is the sole coding exon of this gene. This variant creates a frame shift starting at codon Tyr801 which is replaced by a proline, and followed by the insertion of an irrelevant peptide from another reading frame before ending in a STOP codon at position 26. This variant is not expected to be subject to nonsense mediated mRNA decay, but is predicted to truncate the protein by greater than 10 percent. The putative truncation event removes an entire functional domain of the protein; the BRCA1 C Terminus (BRCT) domain (PF00533). This variant has not been previously reported in the medical literature, is absent from the ClinVar and HGMD mutation databases and is not recorded in gnomAD. Each parent of the proband is heterozygous for the variant . ACMG Classification. the LIG4:c.2401_2410del | p.(Tyr801Profs*26) variant is classified as likely pathogenic as it has the following properties: PVS1_strong: the deleted region is critical to protein function PM2: Absent from controls PM3_supporting: Homozygous LoF variants |