ClinVar Miner

Submissions for variant NM_002312.3(LIG4):c.2440C>T (p.Arg814Ter) (rs104894419)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623453 SCV000741757 pathogenic Inborn genetic diseases 2016-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000008112 SCV000537725 likely pathogenic Lig4 syndrome 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)
Fulgent Genetics,Fulgent Genetics RCV000763320 SCV000893997 pathogenic Lig4 syndrome; Multiple myeloma 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000399723 SCV000329400 pathogenic not provided 2016-04-26 criteria provided, single submitter clinical testing The R814X nonsense pathogenic variant has been reported previously in association with LIG4-relateddisorders (O'Driscoll et al., 2001; Ben-Omran et al., 2005; Stewart et al., 2014). This variant is predicted tocause loss of normal protein function by production of a truncated protein where the last 98 normal aminoacids have been removed.
Invitae RCV000008112 SCV000762706 pathogenic Lig4 syndrome 2018-01-17 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the LIG4 gene (p.Arg814*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 98 amino acids of the LIG4 protein. This variant is present in population databases (rs104894419, ExAC 0.01%). This variant has been reported to segregate with Ligase IV syndrome in several families (PMID: 11779494, 27063650). This variant has also been identified in a homozygous or compound heterozygous state in several individuals affected with Ligase IV syndrome, Seckel syndrome, Dubowitz syndrome, dyskeratosis congenita, and microcephalic primordial dwarfism (PMID: 11779494, 27063650, 16088910, 25239263, 27612988, 24123394). ClinVar contains an entry for this variant (Variation ID: 7673). Experimental studies have shown that this nonsense change results in increased cellular radiosensitivity, diminished cell survival, decreased binding to XRCC4, increased DNA damage, and delayed kinetics of DNA repair (PMID: 15333585, 27063650, 24892279). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000399723 SCV000590842 pathogenic not provided 2016-01-06 criteria provided, single submitter clinical testing
OMIM RCV000008112 SCV000028317 pathogenic Lig4 syndrome 2005-09-01 no assertion criteria provided literature only

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