Submissions for variant NM_206937.2(LIG4):c.220C>T (p.Gln74Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Human Genome Lab, NIMHANS, National Institute of Mental Health and Neuro Sciences	RCV003232906	SCV003928209	likely pathogenic	DNA ligase IV deficiency		criteria provided, single submitter	clinical testing	The stop gained NM_002312.3(LIG4):c.220C>T (p.Gln74Ter) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Gln74Ter variant is novel (not in any individuals) in 1kG All. The p.Gln74Ter variant is novel (not in any individuals) in gnomAD as well as in our inhouse database. This variant is predicted to cause loss of normal protein function through protein truncation. There are 27 downstream pathogenic loss of function variants, with the furthest variant being 740 residues downstream of this variant. This indicates that the region is critical to protein function. The p.Gln74Ter variant is a loss of function variant in the gene LIG4, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_002303.2:p.R25* and 20 others. In addition, the clinical phenotype of the proband matches with that of the disorder caused by pathogenic variants in the LIG4 gene. For these reasons, this variant has been classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003232906	SCV004404913	pathogenic	DNA ligase IV deficiency	2023-08-05	criteria provided, single submitter	clinical testing	This variant disrupts a region of the LIG4 protein in which other variant(s) (p.Gln904*) have been determined to be pathogenic (PMID: 34630384). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 2504115). This variant has not been reported in the literature in individuals affected with LIG4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln74*) in the LIG4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 838 amino acid(s) of the LIG4 protein. For these reasons, this variant has been classified as Pathogenic.