ClinVar Genomic variation as it relates to human health
NM_206937.2(LIG4):c.1271_1275del (p.Lys424fs)
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
-
NM_206937.2(LIG4):c.1271_1275del (p.Lys424fs)
Variation ID: 279838 Accession: VCV000279838.45
- Type and length
-
Deletion, 5 bp
- Location
-
Cytogenetic: 13q33.3 13: 108209994-108209998 (GRCh38) [ NCBI UCSC ] 13: 108862342-108862346 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Dec 6, 2016 Apr 15, 2024 Jan 25, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_206937.2:c.1271_1275del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_996820.1:p.Lys424fs frameshift NM_001098268.2:c.1271_1275del NP_001091738.1:p.Lys424fs frameshift NM_001330595.2:c.1070_1074del NP_001317524.1:p.Lys357fs frameshift NM_001352598.2:c.1271_1275del NP_001339527.1:p.Lys424fs frameshift NM_001352599.2:c.1271_1275del NP_001339528.1:p.Lys424fs frameshift NM_001352600.2:c.1271_1275del NP_001339529.1:p.Lys424fs frameshift NM_001352601.2:c.1271_1275del NP_001339530.1:p.Lys424fs frameshift NM_001352602.2:c.1271_1275del NP_001339531.1:p.Lys424fs frameshift NM_001352603.1:c.1271_1275del NP_001339532.1:p.Lys424fs frameshift NM_001352604.2:c.1307_1311del NP_001339533.1:p.Lys436fs frameshift NM_001379095.1:c.1271_1275del NP_001366024.1:p.Lys424fs frameshift NM_002312.3:c.1271_1275del NP_002303.2:p.Lys424fs frameshift NM_002312.3:c.1271_1275delAAAGA NC_000013.11:g.108209995_108209999del NC_000013.10:g.108862343_108862347del NG_007396.1:g.10537_10541del LRG_79:g.10537_10541del LRG_79t1:c.1271_1275del LRG_79p1:p.Lys424fs - Protein change
- K357fs, K424fs, K436fs
- Other names
- -
- Canonical SPDI
- NC_000013.11:108209993:TCTTTT:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
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 | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
LIG4 | - | - |
GRCh38 GRCh37 |
697 | 813 |
Conditions - Germline
Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 18, 2017 | RCV000267680.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 3, 2023 | RCV000338918.19 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 25, 2024 | RCV000768258.13 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 18, 2022 | RCV002494809.3 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(May 18, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
DNA ligase IV deficiency
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV000898795.1
First in ClinVar: Apr 25, 2019 Last updated: Apr 25, 2019 |
Comment:
LIG4 NM_002312.3 exon 2 p.Lys424Argfs*20 (c.1271_1275del): This variant has been reported as compound heterozygous in the literature in at least 11 individuals with features of … (more)
LIG4 NM_002312.3 exon 2 p.Lys424Argfs*20 (c.1271_1275del): This variant has been reported as compound heterozygous in the literature in at least 11 individuals with features of LIG4 syndrome (most commonly immunodeficiency and failure to thrive), segregating with disease in at least 3 affected family members (Buck 2006 PMID:16358361, Enders 2006 PMID:16585603, Murray 2014 PMID:24123394, Cifaldi 2016 PMID:27893162, Jiang 2016 PMID:26762768, Walne 2016 PMID:27612988). This variant is present in 27/126568 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs772226399). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:279838). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, functional studies suggest that this variant may result in increased sensitivity to radiation (Buck 2006 PMID:16358361, Enders 2006 PMID:16585603, Murray 2014 PMID:24123394, Cifaldi 2016 PMID:27893162). This variant represents a deletion of 5 nucelotides and creates a premature stop codon 20 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene. In summary, this variant is classified as pathogenic. (less)
|
|
Pathogenic
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
LIG4-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000382212.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The LIG4 c.1271_1275delAAAGA (p.Lys424ArgfsTer20) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Lys424ArgfsTer20 variant has been … (more)
The LIG4 c.1271_1275delAAAGA (p.Lys424ArgfsTer20) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Lys424ArgfsTer20 variant has been reported in five studies in which it is found in a compound heterozygous state in 14 individuals with LIG4-related disorders from 11 unrelated families (Buck et al. 2006; Enders et al. 2006; Murray et al. 2014; Jiang et al. 2016; Walne et al. 2016). In all cases, the p.Lys424ArgfsTer20 variant was inherited from a healthy heterozygous parent. Two of these patients were diagnosed with dyskeratosis congenita; the authors state that clinical symptoms in these patients had substantial overlap with LIG4 syndrome (Walne et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00029 in the African population of the Exome Aggregation Consortium. Buck et al. (2006) showed that Lig4 protein expression in fibroblasts from one patient was significantly reduced compared to wild type, and a cell survival assay in fibroblasts from a second patient showed increased sensitivity to ionizing radiation. Based on the evidence and potential impact of frameshift variants, the p.Lys424ArgfsTer20 is classified as pathogenic for LIG4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
DNA ligase IV deficiency
Affected status: yes
Allele origin:
paternal
|
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles
Accession: SCV000998523.1
First in ClinVar: Mar 14, 2020 Last updated: Mar 14, 2020 |
|
|
Pathogenic
(Feb 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
DNA ligase IV deficiency
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512392.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PVS1 very strong, PS4 moderate, PM3 very strong, PP1 moderate
Geographic origin: Brazil
|
|
Pathogenic
(Dec 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
LIG4-Related Disorders
Affected status: unknown
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746932.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 11, 2022 |
Age: 30-39 years
Sex: female
Geographic origin: Iran
|
|
Pathogenic
(Apr 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple myeloma
DNA ligase IV deficiency
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002801055.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Mar 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
DNA ligase IV deficiency
Multiple myeloma
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003924219.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
LIG4 NM_002312.3 exon 2 p.Lys424Argfs*20 (c.1271_1275del): This variant has been reported as compound heterozygous in the literature in at least 11 individuals with features of … (more)
LIG4 NM_002312.3 exon 2 p.Lys424Argfs*20 (c.1271_1275del): This variant has been reported as compound heterozygous in the literature in at least 11 individuals with features of LIG4 syndrome (most commonly immunodeficiency and failure to thrive), segregating with disease in at least 3 affected family members (Buck 2006 PMID:16358361, Enders 2006 PMID:16585603, Murray 2014 PMID:24123394, Cifaldi 2016 PMID:27893162, Jiang 2016 PMID:26762768, Walne 2016 PMID:27612988). This variant is present in 27/126568 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs772226399). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:279838). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, functional studies suggest that this variant may result in increased sensitivity to radiation (Buck 2006 PMID:16358361, Enders 2006 PMID:16585603, Murray 2014 PMID:24123394, Cifaldi 2016 PMID:27893162). This variant represents a deletion of 5 nucelotides and creates a premature stop codon 20 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene. In summary, this variant is classified as pathogenic. (less)
|
|
Pathogenic
(Oct 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329399.6
First in ClinVar: Dec 06, 2016 Last updated: Nov 25, 2023 |
Comment:
Published functional studies demonstrate a damaging effect on Lig4 protein levels (Buck et al., 2006); Frameshift variant predicted to result in protein truncation, as the … (more)
Published functional studies demonstrate a damaging effect on Lig4 protein levels (Buck et al., 2006); Frameshift variant predicted to result in protein truncation, as the last 488 amino acids are replaced with 19 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 27893162, 26762768, 16358361, 27612988, 16585603, 24123394, 30719430, 31696992, 31980526, 34426522, 29146883, 32471509, 31589614, 35595529, 34313030, 34630384, 35665479, 37437665, 36221079) (less)
|
|
Pathogenic
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
DNA ligase IV deficiency
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001235136.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Lys424Argfs*20) 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.Lys424Argfs*20) in the LIG4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 488 amino acid(s) of the LIG4 protein. This variant is present in population databases (rs772226399, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of LIG4 syndrome (PMID: 16358631, 24123394, 27612988, 27893162, 29146883). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as K424fs. ClinVar contains an entry for this variant (Variation ID: 279838). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jan 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249660.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Comment:
LIG4: PVS1, PM3, PM2:Supporting
Number of individuals with the variant: 2
|
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 |
---|---|---|---|---|
A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. | Bluteau O | Blood | 2018 | PMID: 29146883 |
DNA ligase IV deficiency: Immunoglobulin class deficiency depends on the genotype. | Dard R | Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology | 2017 | PMID: 28039949 |
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 |
Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis. | Walne AJ | Haematologica | 2016 | PMID: 27612988 |
Molecular and immunological characterization of DNA ligase IV deficiency. | Jiang J | Clinical immunology (Orlando, Fla.) | 2016 | PMID: 26762768 |
Extreme growth failure is a common presentation of ligase IV deficiency. | Murray JE | Human mutation | 2014 | PMID: 24123394 |
A severe form of human combined immunodeficiency due to mutations in DNA ligase IV. | Enders A | Journal of immunology (Baltimore, Md. : 1950) | 2006 | PMID: 16585603 |
Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV. | Buck D | European journal of immunology | 2006 | PMID: 16358361 |
[Diagnosis and treatment of hypertension. Individual aims, flexible control]. | Zidek W | MMW Fortschritte der Medizin | 2005 | PMID: 16358631 |
Text-mined citations for rs772226399 ...
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.