Submissions for variant NM_206937.2(LIG4):c.833G>C (p.Arg278Pro)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003509003	SCV004296525	likely pathogenic	DNA ligase IV deficiency	2023-06-20	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with atypical severe combined immunodeficiency (PMID: 21664875). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 278 of the LIG4 protein (p.Arg278Pro). This variant is not present in population databases (gnomAD no frequency). 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. This variant disrupts the p.Arg278 amino acid residue in LIG4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26762768). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.