LAT
protein-codinglinker for activation of T cells
Gene summary
The protein encoded by this gene is phosphorylated by ZAP-70/Syk protein tyrosine kinases following activation of the T-cell antigen receptor (TCR) signal transduction pathway. This transmembrane protein localizes to lipid rafts and acts as a docking site for SH2 domain-containing proteins. Upon phosphorylation, this protein recruits multiple adaptor proteins and downstream signaling molecules into multimolecular signaling complexes located near the site of TCR engagement. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~6.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0044721
Submitter: ClinGen
LAT was first reported in relation to autosomal recessive severe combined immunodeficiency due to LAT deficiency in 2016 (Keller et al., PMID: 27242165). Affected individuals have T-B+NK+ severe combined immunodeficiency (SCID), lymphadenopathy (with distorted architecture and absent germinal centers), hypogammaglobulinemia, and autoimmune hematologic conditions leading to failure to thrive, severe recurrent infections and splenomegaly. Most affected individuals require bone marrow transplant for survival. Three frameshift variants that have been reported in three probands in three publications (PMIDs: 27242165, 27522155, 37516813) are included in this curation. Variants in this gene segregated with disease in 4 additional family members. Heterozygous family members did not have symptoms and had normal LAT function, indicating there is no haploinsufficiency effect. The mechanism of pathogenicity is known to be loss of function. This gene-disease association is also supported by mouse model, protein interactions, expression studies, biochemical function, functional alteration, and rescue studies in cell culture models (PMIDs: 9489702, 10204488, 27522155, 9846483, 10360968). LAT is expressed in T cells, NK cells, and mast cells, but not in B cells or monocytes. When LAT was co-expressed with Lck, Fyn, Syk and ZAP-70 in COS cells, Syc and ZAP-70 showed increased activity toward LAT where Lck and Fyn showed negligible activity. In addition, LAT binds to PLC-γ1, Grb2, and PI3K. Overexpression of LAT mutants blocked TCR-mediated AP-1 and NF-AT transcriptional activity (PMID: 9489702). In vitro expression studies showed disrupted downstream signaling, failure of CD69 upregulation and absence of calcium flux induction upon stimulation, as well as absence of downstream tyrosine phosphorylation (PMID: 27522155). LAT -/- mice had absent T cells, normal B cells. Thymocyte numbers were 10-20 fold lower than in LAT het and LAT WT mice. LAT -/- thymocytes fail to develop beyond the DN CD25+CD44- stage, and there were no mature alpha beta T cells in the lymph nodes and spleens of these mice (PMID: 10204488). Two cell culture models with significantly reduced LAT expression (ANJ3 and J.CaM2) showed rescue of TCR signaling after re-expression of LAT (PMID: 9846483, 10360968). This gene-disease pair was originally evaluated by the SCID-CID GCEP on 5/10/2022. It was reevaluated on 9/18/2025. As a result of this reevaluation, the classification changed from strong to definitive with the addition of new case-level genetic evidence (PMID: 37516813).
Inheritance Pattern: AR
Disease ID:MONDO:0044721
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0044721
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious
Intervention: Allergy/Immunology/Infectious
Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; HSCT has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to LAT variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001014987.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 53 | 55 | |||
| missense | 67 | 5 | 72 | |||
| nonsense | 2 | 2 | 4 | |||
| start loss | 0 | |||||
| frameshift | 5 | 1 | 6 | |||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 7 | 1 | 73 | 58 | 0 | 139 |
Highest pathogenic variant AF is 0.000002478533
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001014987.1 | 11 | MANE Select | |
| Ensembl | ENSP00000378841.3 | 11 | MANE Select | |
| RefSeq | NP_001014988.1 | 11 | Standard | |
| RefSeq | NP_001014989.2 | 12 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- T cell receptor signaling pathway - Homo sapiens (human)
- Fc epsilon RI signaling pathway - Homo sapiens (human)
- Fc gamma R-mediated phagocytosis - Homo sapiens (human)
- Th17 cell differentiation - Homo sapiens (human)
- Th1 and Th2 cell differentiation - Homo sapiens (human)
Biological Process
- MAPK cascade
- adaptive immune response
- lymphocyte homeostasis
- inflammatory response
- immune response
Molecular Function
- SH3/SH2 adaptor activity
- Ras guanyl-nucleotide exchange factor activity
- protein binding
- protein kinase binding
Cellular Component
- immunological synapse
- Golgi apparatus
- plasma membrane
- cell-cell junction
- COP9 signalosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000395461
- Coding exons
- 12
- Length
- 5958
- Individuals with no LoFs
- 125725
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 15
- Defined
- 125740
- p
- 0.0000596
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.628 | 143 | 166 | 0.863 | 0.0000100 | 1712 |
| Missense (PolyPhen) | 30 | 45.599 | 0.65791 | 494 | ||
| Synonymous | 0.159 | 68 | 69.7 | 0.976 | 0.00000467 | 546 |
| Loss of Function | 2.68 | 7 | 19.9 | 0.351 | 0.00000112 | 202 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0.00021 | 0.00020 | rare |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000026 | 0.000026 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Required for TCR (T-cell antigen receptor)- and pre-TCR- mediated signaling, both in mature T-cells and during their development. Involved in FCGR3 (low affinity immunoglobulin gamma Fc region receptor III)-mediated signaling in natural killer cells and FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Couples activation of these receptors and their associated kinases with distal intracellular events such as mobilization of intracellular calcium stores, PKC activation, MAPK activation or cytoskeletal reorganization through the recruitment of PLCG1, GRB2, GRAP2, and other signaling molecules. {ECO:0000269|PubMed:10072481}.;
- Disease
- DISEASE: Immunodeficiency 52 (IMD52) [MIM:617514]: An autosomal recessive primary immunodeficiency characterized by T-cell abnormalities, resulting in severe combined immunodeficiency, autoimmune disease, progressive lymphopenia and hypogammaglobulinemia, and lymphoproliferation with splenomegaly. Patients develop severe recurrent infections from infancy. {ECO:0000269|PubMed:27242165, ECO:0000269|PubMed:27522155}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.0956
- RVIS EVS
- -0.54
- RVIS percentile EVS
- 20.54
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.383
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |