NM_206937.2(LIG4):c.2305dup (p.Thr769fs) AND DNA ligase IV deficiency

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 26, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001043969.9

Allele description [Variation Report for NM_206937.2(LIG4):c.2305dup (p.Thr769fs)]

NM_206937.2(LIG4):c.2305dup (p.Thr769fs)

Gene:

LIG4:DNA ligase 4 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

13q33.3

Genomic location:

Preferred name:

NM_206937.2(LIG4):c.2305dup (p.Thr769fs)

HGVS:

NC_000013.11:g.108208964dup
NG_007396.1:g.11571dup
NM_001098268.2:c.2305dup
NM_001330595.2:c.2104dup
NM_001352598.2:c.2305dup
NM_001352599.2:c.2305dup
NM_001352600.2:c.2305dup
NM_001352601.2:c.2305dup
NM_001352602.2:c.2305dup
NM_001352603.1:c.2305dup
NM_001352604.2:c.2341dup
NM_001379095.1:c.2305dup
NM_002312.3:c.2305dup
NM_206937.2:c.2305dupMANE SELECT
NP_001091738.1:p.Thr769fs
NP_001317524.1:p.Thr702fs
NP_001339527.1:p.Thr769fs
NP_001339528.1:p.Thr769fs
NP_001339529.1:p.Thr769fs
NP_001339530.1:p.Thr769fs
NP_001339531.1:p.Thr769fs
NP_001339532.1:p.Thr769fs
NP_001339533.1:p.Thr781fs
NP_001366024.1:p.Thr769fs
NP_002303.2:p.Thr769fs
NP_996820.1:p.Thr769fs
LRG_79t1:c.2305dup
LRG_79:g.11571dup
LRG_79p1:p.Thr769fs
NC_000013.10:g.108861311_108861312insT
NC_000013.10:g.108861312dup

Protein change:

T702fs

Links:

dbSNP: rs1878251067

NCBI 1000 Genomes Browser:

rs1878251067

Molecular consequence:

NM_001098268.2:c.2305dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001330595.2:c.2104dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001352598.2:c.2305dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001352599.2:c.2305dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001352600.2:c.2305dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001352601.2:c.2305dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001352602.2:c.2305dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001352603.1:c.2305dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001352604.2:c.2341dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001379095.1:c.2305dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_002312.3:c.2305dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_206937.2:c.2305dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: DNA ligase IV deficiency
Synonyms:: Lig4 syndrome
Identifiers:: MONDO: MONDO:0011686; MedGen: C1847827; Orphanet: 99812; OMIM: 606593

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001207741	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 26, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11779494, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001207741

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 26, 2019)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency.

O'Driscoll M, Cerosaletti KM, Girard PM, Dai Y, Stumm M, Kysela B, Hirsch B, Gennery A, Palmer SE, Seidel J, Gatti RA, Varon R, Oettinger MA, Neitzel H, Jeggo PA, Concannon P.

Mol Cell. 2001 Dec;8(6):1175-85.

PubMed [citation]

PMID:: 11779494

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001207741.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the LIG4 protein. Other variant(s) that disrupt this region (p.Arg814*) have been determined to be pathogenic (PMID: 11779494,¬†27063650,¬†15333585,¬†23337116,¬†24123394). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with LIG4-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the LIG4 gene (p.Thr769Asnfs*14). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 143 amino acids of the LIG4 protein.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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