ClinVar Genomic variation as it relates to human health
NM_206937.2(LIG4):c.1904del (p.Lys635fs)
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.1904del (p.Lys635fs)
Variation ID: 418659 Accession: VCV000418659.17
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 13q33.3 13: 108209365 (GRCh38) [ NCBI UCSC ] 13: 108861713 (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 27, 2017 May 1, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_206937.2:c.1904del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_996820.1:p.Lys635fs frameshift NM_001098268.2:c.1904del NP_001091738.1:p.Lys635fs frameshift NM_001330595.2:c.1703del NP_001317524.1:p.Lys568fs frameshift NM_001352598.2:c.1904del NP_001339527.1:p.Lys635fs frameshift NM_001352599.2:c.1904del NP_001339528.1:p.Lys635fs frameshift NM_001352600.2:c.1904del NP_001339529.1:p.Lys635fs frameshift NM_001352601.2:c.1904del NP_001339530.1:p.Lys635fs frameshift NM_001352602.2:c.1904del NP_001339531.1:p.Lys635fs frameshift NM_001352603.1:c.1904del NP_001339532.1:p.Lys635fs frameshift NM_001352604.2:c.1940del NP_001339533.1:p.Lys647fs frameshift NM_001379095.1:c.1904del NP_001366024.1:p.Lys635fs frameshift NM_002312.3:c.1904del NP_002303.2:p.Lys635fs frameshift NM_002312.3:c.1904delA NC_000013.11:g.108209366del NC_000013.10:g.108861714del NG_007396.1:g.11170del LRG_79:g.11170del LRG_79t1:c.1904del LRG_79p1:p.Lys635fs - Protein change
- K568fs, K635fs, K647fs
- Other names
- p.Lys635Argfs*10
- Canonical SPDI
- NC_000013.11:108209364:TT: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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0.00060 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
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 |
699 | 816 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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 (4) |
criteria provided, multiple submitters, no conflicts
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May 19, 2022 | RCV000480290.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000641087.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 31, 2021 | RCV002525777.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 11, 2023 | RCV004535497.1 |
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
Help
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
Help
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
Help
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
(Jun 19, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000610969.1
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
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Pathogenic
(Mar 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000860208.1
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Dec 12, 2018)
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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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GeneDx
Accession: SCV000565882.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 17, 2019 |
Comment:
The c.1904delA variant in the LIG4 gene has been reported previously in two individuals with LIG4-related disorders who were compound heterozygous for the c.1904delA variant … (more)
The c.1904delA variant in the LIG4 gene has been reported previously in two individuals with LIG4-related disorders who were compound heterozygous for the c.1904delA variant and another loss of function variant (Jspeert et al., 2013; Bluteau et al., 2018). The c.1904delA variant causes a frameshift starting with codon Lysine 635, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 10 of the new reading frame, denoted p.Lys635ArgfsX10. This variant is predicted to cause loss of normal protein function through protein truncation of the C-terminal region required for XRCC4 binding and LIG4 stability and activity (Jspeert et al., 2013). The c.1904delA variant is observed in 21/24,016 (0.0874%) alleles from individuals of African background in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). We interpret c.1904delA as a pathogenic variant. (less)
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Pathogenic
(Jan 19, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003800906.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(May 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226881.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP4, PM1, PM2_supporting, PM3, PVS1_strong
Number of individuals with the variant: 1
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Pathogenic
(Dec 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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DNA ligase IV deficiency
Affected status: yes
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004244578.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
PVS1_Moderate, PS3_Moderate, PM1, PM3_Strong
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Pathogenic
(Jan 31, 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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Invitae
Accession: SCV000762705.5
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
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, … (more)
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. (less)
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Pathogenic
(Dec 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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LIG4-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004727747.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Aug 31, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003675974.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
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, … (more)
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. (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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Case Report: Wide Spectrum of Manifestations of Ligase IV Deficiency: Report of 3 Cases. | Castro ACE | Frontiers in immunology | 2022 | PMID: 35592332 |
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. | Bluteau O | Blood | 2018 | PMID: 29146883 |
Unique heterozygous presentation in an infant with DNA ligase IV syndrome. | Brunet BA | Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology | 2017 | PMID: 28866308 |
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 |
Extreme growth failure is a common presentation of ligase IV deficiency. | Murray JE | Human mutation | 2014 | PMID: 24123394 |
Clinical spectrum of LIG4 deficiency is broadened with severe dysmaturity, primordial dwarfism, and neurological abnormalities. | IJspeert H | Human mutation | 2013 | PMID: 24027040 |
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 |
DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. | O'Driscoll M | Molecular cell | 2001 | PMID: 11779494 |
Binding and internalization of gold-labeled IFN-gamma by human Raji cells. | Filgueira L | Journal of immunology (Baltimore, Md. : 1950) | 1989 | PMID: 2523926 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LIG4 | - | - | - | - |
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Text-mined citations for rs375554612 ...
HelpRecord last updated May 27, 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.