Submissions for variant NM_206937.2(LIG4):c.2592_2595del (p.Ile864fs)

dbSNP: rs765317127

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519485	SCV000621701	uncertain significance	not provided	2017-10-11	criteria provided, single submitter	clinical testing	The c.2592_2595delAATT variant in the LIG4 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant causes a frameshift starting with codon Isoleucine 864, changes this amino acid to a Methionine residue, and creates a premature Stop codon at position 25 of the new reading frame, denoted p.Ile864MetfsX25. This variant is predicted to cause loss of normal protein function through protein truncation. The c.2592_2595delAATT variant is observed in 5/111,658 alleles (0.0045%) from individuals of non-Finnish European ancestry in the gnomAD dataset (Lek et al., 2016). We interpret c.2592_2595delAATT as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704058	SCV000832991	pathogenic	DNA ligase IV deficiency	2024-11-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile864Metfs*25) in the LIG4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the LIG4 protein. This variant is present in population databases (rs765317127, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with LIG4-related conditions. ClinVar contains an entry for this variant (Variation ID: 452857). 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. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005239131	SCV005884494	pathogenic	Severe combined immunodeficiency disease	2024-12-24	criteria provided, single submitter	clinical testing	Variant summary: LIG4 c.2592_2595delAATT (p.Ile864MetfsX25) results in a premature termination codon, predicted to cause a truncation of the encoded protein and predicted not involved in nonsense-mediated mRNA decay. The variant allele was found at a frequency of 2.8e-05 in 251370 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2592_2595delAATT in individuals affected with Severe Combined Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported. However, at least one nonsense variant has been found in one patient with LIG4 deficiency in HGMD (PMID: 34630384) and pathogenic variants downstream of this variant have been reported in ClinVar. ClinVar contains an entry for this variant (Variation ID: 452857). Based on the evidence outlined above, the variant was classified as pathogenic.
GenomeConnect - Invitae Patient Insights Network	RCV001535528	SCV001749495	not provided	LIG4-related disorder		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 04-25-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.