Submissions for variant NM_206937.2(LIG4):c.1904del (p.Lys635fs)

dbSNP: rs375554612

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480290	SCV000565882	pathogenic	not provided	2024-11-26	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in abnormal protein length as the last 277 amino acids are replaced with 9 different amino acids, and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 24123394, 31589614, 24027040, 29146883, 35592332, 35503492, 27612988, 24892279, 11779494, 28866308)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000480290	SCV000610969	pathogenic	not provided	2017-06-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000641087	SCV000762705	pathogenic	DNA ligase IV deficiency	2024-12-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys635Argfs*10) in the LIG4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 277 amino acid(s) of the LIG4 protein. This variant is present in population databases (rs375554612, gnomAD 0.09%). This premature translational stop signal has been observed in individual(s) with LIG4 deficiency and bone marrow failure (PMID: 24027040, 28866308, 29146883). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 418659). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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, 27612988). 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.
Eurofins Ntd Llc (ga)	RCV000480290	SCV000860208	pathogenic	not provided	2018-03-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002525777	SCV003675974	pathogenic	Inborn genetic diseases	2021-08-31	criteria provided, single submitter	clinical testing	The c.1904delA (p.K635Rfs*10) alteration, located in exon 2 (coding exon 1) of the LIG4 gene, consists of a deletion of one nucleotide at position 1904, causing a translational frameshift with a predicted alternate stop codon after 10 amino acids. Frameshifts are typically deleterious in nature; however, because LIG4 is a single-exon gene, this alteration is not expected to trigger nonsense-mediated mRNA decay and a(n) altered/truncated protein could still be expressed (Maquat, 2004). This alteration impacts a significant portion of the protein and the impacted region is critical for protein function (Ambry internal data). Based on data from gnomAD, this allele has an overall frequency of 0.01% (23/282740) total alleles studied. The highest observed frequency was 0.08% (21/24954) of African alleles. This mutation has been reported in conjunction with a second LIG4 alteration in several individuals with LIG4 syndrome (IJspeert, 2013; Brunet, 2017; Bluteau, 2018). In addition, a downstream truncation alteration, p.R814* c.2440C>T, has been described in individuals with LIG4 syndrome (O'Driscoll, 2001; Ben-Omran, 2005; Walne, 2016). Based on the available evidence, this alteration is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000641087	SCV003800906	pathogenic	DNA ligase IV deficiency	2023-01-19	criteria provided, single submitter	clinical testing	Variant summary: LIG4 c.1904delA (p.Lys635ArgfsX10) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with LIG4 syndrome in HGMD. The variant allele was found at a frequency of 6e-05 in 251356 control chromosomes. c.1904delA has been reported in the literature in individuals affected with LIG4 Syndrome and deficiency (Brunet_2017, IJspeert_2013, Castro_2022) as well as Microcephalic Primordial Dwarfism (Murry_ 2014) and Bone Marrow Failure (Bluteau_2018), both of which can be presentations of LIG4 deficiency. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000480290	SCV004226881	pathogenic	not provided	2022-05-19	criteria provided, single submitter	clinical testing	PP4, PM1, PM2_supporting, PM3, PVS1_strong
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000641087	SCV004244578	pathogenic	DNA ligase IV deficiency	2023-12-20	criteria provided, single submitter	clinical testing	PVS1_Moderate, PS3_Moderate, PM1, PM3_Strong
Fulgent Genetics, Fulgent Genetics	RCV005010384	SCV005632802	pathogenic	DNA ligase IV deficiency; Multiple myeloma	2024-03-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535497	SCV004727747	pathogenic	LIG4-related disorder	2023-12-11	no assertion criteria provided	clinical testing	The LIG4 c.1904delA variant is predicted to result in a frameshift and premature protein termination (p.Lys635Argfs*10). This variant was reported together with second LIG4 loss-of-function variant in several individuals with LIG4 deficiency (Ijspeert et al. 2013. PubMed ID: 24027040; Brunet et al. 2017. PubMed ID: 28866308; TableS8 and 14; Bluteau et al. 2017. PubMed ID: 29146883). This variant is reported in 0.084% of alleles in individuals of African descent in gnomAD. Frameshift variants in LIG4 are expected to be pathogenic. This variant is interpreted as pathogenic.