ClinVar Miner

Submissions for variant NM_206937.2(LIG4):c.56T>G (p.Leu19Trp)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002604251 SCV002952980 uncertain significance DNA ligase IV deficiency 2021-12-22 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 19 of the LIG4 protein (p.Leu19Trp). This variant is present in population databases (rs765520147, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with LIG4-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004801229 SCV005422933 uncertain significance not specified 2024-10-08 criteria provided, single submitter clinical testing Variant summary: LIG4 c.56T>G (p.Leu19Trp) results in a non-conservative amino acid change located in the DNA ligase, ATP-dependent, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249468 control chromosomes. c.56T>G has been reported in the literature in individuals affected with severe aplastic anemia and ligase IV deficiency (e.g., Castro_2022, McReynolds_2022, Fridlyand_2023). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35592332, 35776903, 35665709). ClinVar contains an entry for this variant (Variation ID: 1920777). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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