ClinVar Genomic variation as it relates to human health
NM_206937.2(LIG4):c.833G>A (p.Arg278His)
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.833G>A (p.Arg278His)
Variation ID: 7675 Accession: VCV000007675.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q33.3 13: 108210436 (GRCh38) [ NCBI UCSC ] 13: 108862784 (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 Jan 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_206937.2:c.833G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_996820.1:p.Arg278His missense NM_001098268.2:c.833G>A NP_001091738.1:p.Arg278His missense NM_001330595.2:c.632G>A NP_001317524.1:p.Arg211His missense NM_001352598.2:c.833G>A NP_001339527.1:p.Arg278His missense NM_001352599.2:c.833G>A NP_001339528.1:p.Arg278His missense NM_001352600.2:c.833G>A NP_001339529.1:p.Arg278His missense NM_001352601.2:c.833G>A NP_001339530.1:p.Arg278His missense NM_001352602.2:c.833G>A NP_001339531.1:p.Arg278His missense NM_001352603.1:c.833G>A NP_001339532.1:p.Arg278His missense NM_001352604.2:c.869G>A NP_001339533.1:p.Arg290His missense NM_001379095.1:c.833G>A NP_001366024.1:p.Arg278His missense NM_002312.3:c.833G>A NP_002303.2:p.Arg278His missense NC_000013.11:g.108210436C>T NC_000013.10:g.108862784C>T NG_007396.1:g.10099G>A LRG_79:g.10099G>A LRG_79t1:c.833G>A LRG_79p1:p.Arg278His P49917:p.Arg278His - Protein change
- R278H, R211H, R290H
- Other names
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- Canonical SPDI
- NC_000013.11:108210435:C:T
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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
Help
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 (3) |
criteria provided, multiple submitters, no conflicts
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Jan 2, 2024 | RCV000008114.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2019 | RCV001092919.21 |
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
(Jan 02, 2024)
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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: SCV003442262.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 278 of the LIG4 protein (p.Arg278His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 278 of the LIG4 protein (p.Arg278His). This variant is present in population databases (rs104894421, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of LIG4 syndrome (PMID: 11779494, 15333585, 27893162, 30719430). 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: 7675). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LIG4 function (PMID: 11779494, 15333585, 26608917). This variant disrupts the p.Arg278 amino acid residue in LIG4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26762768). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 13, 2020)
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criteria provided, single submitter
Method: clinical testing
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DNA ligase IV deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764777.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Microcephaly (present) , Hepatosplenomegaly (present) , Spastic ataxia (present) , Progressive cerebellar ataxia (present) , Cirrhosis of liver (present) , Pancytopenia (present) , Axial dystonia … (more)
Microcephaly (present) , Hepatosplenomegaly (present) , Spastic ataxia (present) , Progressive cerebellar ataxia (present) , Cirrhosis of liver (present) , Pancytopenia (present) , Axial dystonia (present) (less)
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Pathogenic
(Jan 01, 2019)
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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: SCV001249661.25
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: SCV000028319.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
O'Driscoll et al. (2001) identified 3 amino acid substitutions in homozygosity in the LIG4 gene of patient 411BR with LIG4 syndrome (606593): ala3 to val, … (more)
O'Driscoll et al. (2001) identified 3 amino acid substitutions in homozygosity in the LIG4 gene of patient 411BR with LIG4 syndrome (606593): ala3 to val, resulting from a C-to-T transition at nucleotide 8, thr9 to ile, resulting from a C-to-T transition at nucleotide 26, and arg278 to his, resulting from a G-to-A transition at nucleotide 833. The arg278-to-his mutation was identical to that identified in patient 180BR, who had leukemia and whose cell line was radiosensitive and defective in double-strand break repair, by Riballo et al. (1999). The arg278 residue lies within a highly conserved motif encompassing the active site, and the substitution was shown to significantly impair LIG4 function (Riballo et al., 2001). The other 2 amino acid substitutions in patient 411BR, ala3 to val (A3V; 601837.0005) and thr9 to ile (T9I; 601837.0006), were considered to be likely polymorphic variants that may have aggravated the resulting phenotype. Patient 411BR, who was 9 years old, had a phenotype that included microcephaly at birth, developmental and mental delay, pancytopenia, and extensive plantar warts. (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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Failing to Make Ends Meet: The Broad Clinical Spectrum of DNA Ligase IV Deficiency. Case Series and Review of the Literature. | Staines Boone AT | Frontiers in pediatrics | 2019 | PMID: 30719430 |
Late-onset combined immune deficiency due to LIGIV mutations in a 12-year-old patient. | Cifaldi C | Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology | 2017 | PMID: 27893162 |
Molecular and immunological characterization of DNA ligase IV deficiency. | Jiang J | Clinical immunology (Orlando, Fla.) | 2016 | PMID: 26762768 |
The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining. | Park J | Journal of immunology (Baltimore, Md. : 1950) | 2016 | PMID: 26608917 |
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 |
Cellular and biochemical impact of a mutation in DNA ligase IV conferring clinical radiosensitivity. | Riballo E | The Journal of biological chemistry | 2001 | PMID: 11349135 |
Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient. | Riballo E | Current biology : CB | 1999 | PMID: 10395545 |
Text-mined citations for rs104894421 ...
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.