ClinVar Miner

Submissions for variant NM_206937.2(LIG4):c.743C>T (p.Pro248Leu)

dbSNP: rs2138978193
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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 RCV001880861 SCV002142774 likely pathogenic DNA ligase IV deficiency 2023-09-10 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LIG4 protein function. ClinVar contains an entry for this variant (Variation ID: 1377838). This missense change has been observed in individual(s) with clinical features of combined immunodeficiency (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 248 of the LIG4 protein (p.Pro248Leu).
Ambry Genetics RCV004041113 SCV004897589 likely pathogenic Inborn genetic diseases 2024-04-17 criteria provided, single submitter clinical testing The c.743C>T (p.P248L) alteration is located in exon 2 (coding exon 1) of the LIG4 gene. This alteration results from a C to T substitution at nucleotide position 743, causing the proline (P) at amino acid position 248 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified in the homozygous state and/or in conjunction with other LIG4 variant(s) in individual(s) with features consistent with LIG4 syndrome; in at least one instance, the variants were identified in trans (external communication). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

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