ClinVar Miner

Submissions for variant NM_206937.2(LIG4):c.2440C>T (p.Arg814Ter)

gnomAD frequency: 0.00007  dbSNP: rs104894419
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000399723 SCV000329400 pathogenic not provided 2022-11-21 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate less than 1% residual activity and significantly impaired interaction with XRCC4 and NAD+ (Girard et al., 2004; Chen et al., 2018); This variant is associated with the following publications: (PMID: 11779494, 27855655, 26608917, 24892279, 27537055, 27353043, 27612988, 25239263, 29146883, 30719430, 30496552, 31130284, 31980526, 33739554, 31589614, 24123394, 16088910, 15333585, 27063650, 23372718)
Center of Genomic medicine, Geneva, University Hospital of Geneva RCV000008112 SCV000537725 likely pathogenic DNA ligase IV deficiency 2014-07-07 criteria provided, single submitter clinical testing This heterozygous variant in the LIG4 gene (autosomal recessive transmission) was identified in a twin pair (one male and one female patient) with extreme growth delay, who also harbours another variant in the LIG4 gene (compound heterozygosity)
Molecular Diagnostics Lab, Nemours Children's Health, Delaware RCV000399723 SCV000590842 pathogenic not provided 2016-01-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000623453 SCV000741757 pathogenic Inborn genetic diseases 2016-08-24 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000008112 SCV000762706 pathogenic DNA ligase IV deficiency 2025-01-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg814*) in the LIG4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 98 amino acid(s) of the LIG4 protein. This variant is present in population databases (rs104894419, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Ligase IV syndrome (PMID: 11779494, 16088910, 24123394, 25239263, 27063650, 27612988). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7673). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects LIG4 function (PMID: 15333585, 24892279, 27063650). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000763320 SCV000893997 pathogenic DNA ligase IV deficiency; Multiple myeloma 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000399723 SCV001249658 pathogenic not provided 2025-01-01 criteria provided, single submitter clinical testing LIG4: PM3:Very Strong, PVS1, PM2
Duke University Health System Sequencing Clinic, Duke University Health System RCV000008112 SCV003919065 pathogenic DNA ligase IV deficiency 2023-04-20 criteria provided, single submitter research
Molecular Genetics laboratory, Necker Hospital RCV003483426 SCV004231898 pathogenic prenatal LIG4 syndrome with aqueductal stenosis 2023-12-28 criteria provided, single submitter clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre RCV000008112 SCV004801153 pathogenic DNA ligase IV deficiency 2024-03-14 criteria provided, single submitter research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000399723 SCV005878845 pathogenic not provided 2024-10-31 criteria provided, single submitter clinical testing The LIG4 c.2440C>T; p.Arg814Ter variant (rs104894419) is reported in the literature in multiple homozygous and compound heterozygous individuals affected with LIG4 syndrome (Ben-Omran 2005, Murray 2014, O’Driscoll 2001). This variant is found in the non-Finnish European population with an allele frequency of 0.02% (24/129,080 alleles) in the Genome Aggregation Database (v2.1.1). This variant results in a premature termination codon in the last exon of the LIG4 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated LIG4 protein. Functional assays demonstrate the variant protein has reduced interaction with binding partners and significantly reduced enzymatic activity (Girard 2004). Based on available information, this variant is considered to be pathogenic. References: Ben-Omran TI et al. A patient with mutations in DNA Ligase IV: clinical features and overlap with Nijmegen breakage syndrome. Am J Med Genet A. 2005 Sep 1;137A(3):283-7. PMID: 16088910. Girard PM et al. Analysis of DNA ligase IV mutations found in LIG4 syndrome patients: the impact of two linked polymorphisms. Hum Mol Genet. 2004 Oct 15;13(20):2369-76. PMID: 15333585. Murray JE et al. Extreme growth failure is a common presentation of ligase IV deficiency. Hum Mutat. 2014 Jan;35(1):76-85. PMID: 24123394. O'Driscoll M et al. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell. 2001 Dec;8(6):1175-85. PMID: 11779494.
OMIM RCV000008112 SCV000028317 pathogenic DNA ligase IV deficiency 2005-09-01 no assertion criteria provided literature only
PreventionGenetics, part of Exact Sciences RCV004532308 SCV004739592 pathogenic LIG4-related disorder 2024-01-03 no assertion criteria provided clinical testing The LIG4 c.2440C>T variant is predicted to result in premature protein termination (p.Arg814*). This variant has been reported in the compound heterozygous state in individuals with ligase IV syndrome (O'Driscoll et al. 2001. PubMed ID: 11779494; Felgentreff et al. 2016. PubMed ID: 27063650). This variant has also been reported in the compound heterozygous state in individuals with atypical Seckel syndrome, Dubowitz syndrome, dyskeratosis congenita, and microcephalic primordial dwarfism (Murray et al. 2014. PubMed ID: 24123394; Zhang et al. 2015. PubMed ID: 25239263; Walne et al. 2016. PubMed ID: 27612988). Functional studies have shown that this variant leads to increased cellular radiosensitivity, diminished cell survival, decreased binding to XRCC4, increased DNA damage, and delayed kinetics of DNA repair (Girard et al. 2004. PubMed ID: 15333585; Stewart et al. 2014. PubMed ID: 24892279; Felgentreff et al. 2016. PubMed ID: 27063650). This variant is reported in 0.019% of alleles in individuals of European (non-Finnish) descent in gnomAD. Nonsense variants in LIG4 are expected to be pathogenic. This variant is interpreted as pathogenic.

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