ClinVar Miner

Submissions for variant NM_206937.2(LIG4):c.1144_1145del (p.Leu382fs)

dbSNP: rs1246940345
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000627441 SCV000748440 likely pathogenic not provided 2018-04-03 criteria provided, single submitter clinical testing The c.1144_1145delCT variant in the LIG4 gene has been reported previously using alternate nomenclature (c.1142-1143delCT) on the opposite allele (in trans) with another LIG4 variant in an individual with autoimmune hemolytic anemia, severe pneumonia, thrombocytopenia, microcephaly, and growth retardation (Jiang et al., 2016). The c.1144_1145delCT variant causes a frameshift starting with codon Leucine 382, changes this amino acid to a Glutamic acid residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Leu382GlufsX5. This variant is predicted to cause loss of normal protein function through protein truncation. The c.1144_1145delCT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.1144_1145delCT as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV001860490 SCV002246100 pathogenic DNA ligase IV deficiency 2024-03-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu382Glufs*5) in the LIG4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 530 amino acid(s) of the LIG4 protein. This variant is present in population databases (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with ligase IV syndrome (PMID: 26762768). ClinVar contains an entry for this variant (Variation ID: 523952). This variant disrupts a region of the LIG4 protein in which other variant(s) (p.Arg814*) have been determined to be pathogenic (PMID: 11779494, 16088910, 25239263, 27063650). 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.
Juno Genomics, Hangzhou Juno Genomics, Inc RCV001860490 SCV005416590 pathogenic DNA ligase IV deficiency criteria provided, single submitter clinical testing PVS1_Strong+PM2_Supporting+PM3_Strong+PP4

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