ClinVar Genomic variation as it relates to human health
NM_206937.2(LIG4):c.1738C>T (p.Arg580Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_206937.2(LIG4):c.1738C>T (p.Arg580Ter)
Variation ID: 7672 Accession: VCV000007672.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q33.3 13: 108209531 (GRCh38) [ NCBI UCSC ] 13: 108861879 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Oct 8, 2024 Dec 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_206937.2:c.1738C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_996820.1:p.Arg580Ter nonsense NM_001098268.2:c.1738C>T NP_001091738.1:p.Arg580Ter nonsense NM_001330595.2:c.1537C>T NP_001317524.1:p.Arg513Ter nonsense NM_001352598.2:c.1738C>T NP_001339527.1:p.Arg580Ter nonsense NM_001352599.2:c.1738C>T NP_001339528.1:p.Arg580Ter nonsense NM_001352600.2:c.1738C>T NP_001339529.1:p.Arg580Ter nonsense NM_001352601.2:c.1738C>T NP_001339530.1:p.Arg580Ter nonsense NM_001352602.2:c.1738C>T NP_001339531.1:p.Arg580Ter nonsense NM_001352603.1:c.1738C>T NP_001339532.1:p.Arg580Ter nonsense NM_001352604.2:c.1774C>T NP_001339533.1:p.Arg592Ter nonsense NM_001379095.1:c.1738C>T NP_001366024.1:p.Arg580Ter nonsense NM_002312.3:c.1738C>T NP_002303.2:p.Arg580Ter nonsense NC_000013.11:g.108209531G>A NC_000013.10:g.108861879G>A NG_007396.1:g.11004C>T LRG_79:g.11004C>T LRG_79t1:c.1738C>T LRG_79p1:p.Arg580Ter - Protein change
- R580*, R513*, R592*
- Other names
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- Canonical SPDI
- NC_000013.11:108209530:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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LIG4 | - | - |
GRCh38 GRCh37 |
705 | 823 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, single submitter
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Dec 3, 2023 | RCV000008111.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2017 | RCV001092918.21 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Dec 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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DNA ligase IV deficiency
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004282763.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg580*) in the LIG4 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg580*) in the LIG4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 332 amino acid(s) of the LIG4 protein. This variant is present in population databases (rs104894418, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with LIG4-related conditions (PMID: 11779494). 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: 7672). Algorithms developed to predict the effect of variants on protein 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, 23337116). This variant disrupts a region of the LIG4 protein in which other variant(s) (p.Arg814*) have been determined to be pathogenic (PMID: 1779494, 5333585, 16088910, 24123394, 24892279, 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. (less)
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Pathogenic
(Feb 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249659.25
First in ClinVar: May 12, 2020 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Dec 01, 2001)
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no assertion criteria provided
Method: literature only
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LIG4 SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028316.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
O'Driscoll et al. (2001) identified a 1738C-T transition of the LIG4 gene in 2 sibs (patients 2303 and 2304) with LIG4 syndrome (606593). The mutation … (more)
O'Driscoll et al. (2001) identified a 1738C-T transition of the LIG4 gene in 2 sibs (patients 2303 and 2304) with LIG4 syndrome (606593). The mutation resulted in an arg580-to-ter substitution (R580X). The patients were compound heterozygotes; the mutation in the other LIG4 allele was R814X (601837.0002). The phenotype of the 2 patients, who were 46 and 48 years old, respectively, included microcephaly, growth retardation, pancytopenia, myelodysplasia, chronic respiratory infections, photosensitivity, telangiectasia, hypothyroidism, type II diabetes, and hypogonadism. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis. | Walne AJ | Haematologica | 2016 | PMID: 27612988 |
Ligase-4 Deficiency Causes Distinctive Immune Abnormalities in Asymptomatic Individuals. | Felgentreff K | Journal of clinical immunology | 2016 | PMID: 27063650 |
Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity. | Zhang MY | Haematologica | 2015 | PMID: 25239263 |
Dubowitz syndrome is a complex comprised of multiple, genetically distinct and phenotypically overlapping disorders. | Stewart DR | PloS one | 2014 | PMID: 24892279 |
Extreme growth failure is a common presentation of ligase IV deficiency. | Murray JE | Human mutation | 2014 | PMID: 24123394 |
A noncatalytic function of the ligation complex during nonhomologous end joining. | Cottarel J | The Journal of cell biology | 2013 | PMID: 23337116 |
A patient with mutations in DNA Ligase IV: clinical features and overlap with Nijmegen breakage syndrome. | Ben-Omran TI | American journal of medical genetics. Part A | 2005 | PMID: 16088910 |
Analysis of DNA ligase IV mutations found in LIG4 syndrome patients: the impact of two linked polymorphisms. | Girard PM | Human molecular genetics | 2004 | PMID: 15333585 |
DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. | O'Driscoll M | Molecular cell | 2001 | PMID: 11779494 |
[The report of clinical statistical studies on registered bladder cancer patients in Japan 1982-1987. Japanese Urological Association, Committee on General Rule for Studies on Bladder Cancer]. | Kakizoe T | Nihon Hinyokika Gakkai zasshi. The japanese journal of urology | 1991 | PMID: 1779494 |
[Immunobiological reactions to streptococci in chronic colitis and enterocolitis]. | Ekisenina NI | Sovetskaia meditsina | 1965 | PMID: 5333585 |
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Text-mined citations for rs104894418 ...
HelpRecord last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.