ClinVar Genomic variation as it relates to human health
NM_206937.2(LIG4):c.613del (p.Ser205fs)
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.613del (p.Ser205fs)
Variation ID: 521262 Accession: VCV000521262.15
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 13q33.3 13: 108210656 (GRCh38) [ NCBI UCSC ] 13: 108863004 (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 15, 2018 Apr 15, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_206937.2:c.613del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_996820.1:p.Ser205fs frameshift NM_206937.2:c.613delT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001098268.2:c.613del NP_001091738.1:p.Ser205fs frameshift NM_001330595.2:c.412del NP_001317524.1:p.Ser138fs frameshift NM_001352598.2:c.613del NP_001339527.1:p.Ser205fs frameshift NM_001352599.2:c.613del NP_001339528.1:p.Ser205fs frameshift NM_001352600.2:c.613del NP_001339529.1:p.Ser205fs frameshift NM_001352601.2:c.613del NP_001339530.1:p.Ser205fs frameshift NM_001352602.2:c.613del NP_001339531.1:p.Ser205fs frameshift NM_001352603.1:c.613del NP_001339532.1:p.Ser205fs frameshift NM_001352604.2:c.649del NP_001339533.1:p.Ser217fs frameshift NM_001379095.1:c.613del NP_001366024.1:p.Ser205fs frameshift NM_002312.3:c.613del NP_002303.2:p.Ser205fs frameshift NM_002312.3:c.613delT NC_000013.11:g.108210659del NC_000013.10:g.108863007del NG_007396.1:g.9879del LRG_79:g.9879del LRG_79t1:c.613del LRG_79p1:p.Ser205fs - Protein change
- S205fs, S217fs, S138fs
- Other names
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- Canonical SPDI
- NC_000013.11:108210655:AAAA:AAA
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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.
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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 |
699 | 816 |
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
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 (1) |
criteria provided, single submitter
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Aug 24, 2016 | RCV000622502.4 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2024 | RCV000690275.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 26, 2021 | RCV001653956.4 |
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
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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
(Jul 26, 2021)
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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: SCV001871201.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
Published functional studies suggest a damaging effect on protein localization, as the protein was expressed in the cytoplasm rather than in the nucleus (IJspeert et … (more)
Published functional studies suggest a damaging effect on protein localization, as the protein was expressed in the cytoplasm rather than in the nucleus (IJspeert et al., 2013); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 707 amino acids are lost and replaced with 28 incorrect amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 24027040, 31604460, 23372718, 30262796, 24892279) (less)
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Pathogenic
(Aug 24, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741756.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Short stature (present) , Microcephaly (present) , Hearing impairment (present) , Hypothyroidism (present) , Growth hormone deficiency (present) , Abnormality of parotid gland (present) , … (more)
Short stature (present) , Microcephaly (present) , Hearing impairment (present) , Hypothyroidism (present) , Growth hormone deficiency (present) , Abnormality of parotid gland (present) , Premature ovarian insufficiency (present) , Osteoporosis (present) , Asthma (present) , Hepatic steatosis (present) , Pancytopenia (present) , Neutropenia (present) , Specific learning disability (present) , Abnormality of the dentition (present) , High pitched voice (present) , Upslanted palpebral fissure (present) , Underdeveloped nasal alae (present) , Depigmentation/hyperpigmentation of skin (present) , Papule (present) , Premature graying of hair (present) , Diabetes insipidus (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
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Pathogenic
(Jul 28, 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: SCV004029420.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Variant summary: LIG4 c.613delT (p.Ser205LeufsX29) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known … (more)
Variant summary: LIG4 c.613delT (p.Ser205LeufsX29) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 5.6e-05 in 250070 control chromosomes (gnomAD). c.613delT has been reported in the literature in individuals affected with LIG4 Syndrome (Murray_2014, Yue_2013, Stewart_2014), and they were reported as compound heterozygous with a (likely) pathogenic variant. These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 24123394, 23372718, 24892279). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 22, 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: SCV000817956.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ser205Leufs*29) 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.Ser205Leufs*29) in the LIG4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 707 amino acid(s) of the LIG4 protein. This variant is present in population databases (rs780879476, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with LIG4-deficiency syndrome and Dubowitz syndrome (PMID: 23372718, 24027040, 24892279). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 521262). 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, 27063650). 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
(Nov 20, 2020)
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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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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503631.2
First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is a deletion of 1 bp in exon 3 (of 3) of LIG4 that is predicted to create a premature termination codon … (more)
This sequence change is a deletion of 1 bp in exon 3 (of 3) of LIG4 that is predicted to create a premature termination codon at position 233 (p.(Ser205Leufs*29)). While this is not anticipated to result in nonsense mediated decay, it is expected to remove greater than 70% of the protein, including regions critical for function (PVS1_Strong; PMID: 24027040).The variant is present in a large population cohort at a frequency of 0.006%, which is consistent with a recessive disorder (PM2; rs780879476, 16/281,468 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified compound heterozygous with a second pathogenic allele in at least three individuals with LIG4 syndrome, and segregates with the condition in at least two families (PM3_Strong, PP1_Moderate; PMID: 23372718, 24027040, 24892279, 31604460). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1_Strong, PM3_Strong, PM2, PP1_Moderate. (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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Allogeneic hematopoietic stem cell transplantation in two brothers with DNA ligase IV deficiency: a case report and review of the literature. | Schober S | BMC pediatrics | 2019 | PMID: 31604460 |
Ligase-4 Deficiency Causes Distinctive Immune Abnormalities in Asymptomatic Individuals. | Felgentreff K | Journal of clinical immunology | 2016 | PMID: 27063650 |
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 |
Clinical spectrum of LIG4 deficiency is broadened with severe dysmaturity, primordial dwarfism, and neurological abnormalities. | IJspeert H | Human mutation | 2013 | PMID: 24027040 |
Identification of the DNA repair defects in a case of Dubowitz syndrome. | Yue J | PloS one | 2013 | PMID: 23372718 |
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 |
Text-mined citations for rs780879476 ...
HelpRecord last updated Apr 15, 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.