Submissions for variant NM_206937.2(LIG4):c.845A>G (p.His282Arg)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003058425	SCV003442772	likely pathogenic	DNA ligase IV deficiency	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 282 of the LIG4 protein (p.His282Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of LIG4 syndrome (PMID: 24027040). ClinVar contains an entry for this variant (Variation ID: 2137540). 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.His282 amino acid residue in LIG4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16585603, 18845326, 31604460). 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.