NM_206937.2(LIG4):c.833G>T (p.Arg278Leu) AND DNA ligase IV deficiency

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 14, 2023
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:: RCV003509002.2

Allele description [Variation Report for NM_206937.2(LIG4):c.833G>T (p.Arg278Leu)]

NM_206937.2(LIG4):c.833G>T (p.Arg278Leu)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

13q33.3

Genomic location:

Preferred name:

NM_206937.2(LIG4):c.833G>T (p.Arg278Leu)

HGVS:

NC_000013.11:g.108210436C>A
NG_007396.1:g.10099G>T
NM_001098268.2:c.833G>T
NM_001330595.2:c.632G>T
NM_001352598.2:c.833G>T
NM_001352599.2:c.833G>T
NM_001352600.2:c.833G>T
NM_001352601.2:c.833G>T
NM_001352602.2:c.833G>T
NM_001352603.1:c.833G>T
NM_001352604.2:c.869G>T
NM_001379095.1:c.833G>T
NM_002312.3:c.833G>T
NM_206937.2:c.833G>TMANE SELECT
NP_001091738.1:p.Arg278Leu
NP_001317524.1:p.Arg211Leu
NP_001339527.1:p.Arg278Leu
NP_001339528.1:p.Arg278Leu
NP_001339529.1:p.Arg278Leu
NP_001339530.1:p.Arg278Leu
NP_001339531.1:p.Arg278Leu
NP_001339532.1:p.Arg278Leu
NP_001339533.1:p.Arg290Leu
NP_001366024.1:p.Arg278Leu
NP_002303.2:p.Arg278Leu
NP_996820.1:p.Arg278Leu
LRG_79t1:c.833G>T
LRG_79:g.10099G>T
LRG_79p1:p.Arg278Leu
NC_000013.10:g.108862784C>A

Protein change:

R211L

Molecular consequence:

NM_001098268.2:c.833G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330595.2:c.632G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352598.2:c.833G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352599.2:c.833G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352600.2:c.833G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352601.2:c.833G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352602.2:c.833G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352603.1:c.833G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352604.2:c.869G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379095.1:c.833G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002312.3:c.833G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_206937.2:c.833G>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV004296524	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 14, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26762768, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004296524

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 14, 2023)

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

Molecular and immunological characterization of DNA ligase IV deficiency.

Jiang J, Tang W, An Y, Tang M, Wu J, Qin T, Zhao X.

Clin Immunol. 2016 Feb;163:75-83. doi: 10.1016/j.clim.2015.12.016. Epub 2016 Jan 4.

PubMed [citation]

PMID:: 26762768

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, SCV004296524.1

#	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. 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. This missense change has been observed in individual(s) with LIG4 syndrome (PMID: 26762768). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.06%). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 278 of the LIG4 protein (p.Arg278Leu).

#	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: Feb 1, 2025

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