severe combined immunodeficiency due to LAT deficiency

Summary

severe combined immunodeficiency due to LAT deficiency (MONDO:0044721) is a disease caused by LAT (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LAT (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 8

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	severe combined immunodeficiency due to LAT deficiency
Mondo ID	MONDO:0044721
OMIM	617514
Orphanet	504523
DOID	DOID:0111983
UMLS	C4479588
MedGen	1384124
GARD	0017938
Is cancer (heuristic)	no

Also known as: IMD52 · SCID due to LAT deficiency

Data availability: 8 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › combined immunodeficiency › severe combined immunodeficiency › T-B+ severe combined immunodeficiency › severe combined immunodeficiency due to LAT deficiency

Related subtypes (9): T-B+ severe combined immunodeficiency due to gamma chain deficiency, combined immunodeficiency, X-linked, T-B+ severe combined immunodeficiency due to JAK3 deficiency, immunodeficiency 104, lung fibrosis-immunodeficiency-46,XX gonadal dysgenesis syndrome, severe combined immunodeficiency due to CORO1A deficiency, T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency, T-B+ severe combined immunodeficiency due to CD45 deficiency, T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

8 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 uncertain significance, 2 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
427750	NM_001014987.2(LAT):c.268_269del (p.Gly90fs)	LAT	Pathogenic	no assertion criteria provided
427751	NM_001014987.2(LAT):c.44dup (p.Leu16fs)	LAT	Pathogenic	no assertion criteria provided
1031728	NM_001014989.2(LAT):c.52dup (p.Ala18fs)	LOC130058751	Pathogenic	criteria provided, single submitter
1028939	NM_001014987.2(LAT):c.422C>T (p.Pro141Leu)	LAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1341885	NM_001014987.2(LAT):c.233T>C (p.Leu78Pro)	LAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1166615	NM_001014987.2(LAT):c.399-9T>A	LAT	Benign	criteria provided, multiple submitters, no conflicts
1168087	NM_001014987.2(LAT):c.318T>C (p.Ser106=)	LAT	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1170584	NM_001014987.2(LAT):c.360G>A (p.Ala120=)	LAT	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
LAT	Definitive	Autosomal recessive	severe combined immunodeficiency due to LAT deficiency	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LAT	Orphanet:504523	Severe combined immunodeficiency due to LAT deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LAT	HGNC:18874	ENSG00000213658	O43561	Linker for activation of T-cells family member 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LAT	Linker for activation of T-cells family member 1	Required for TCR (T-cell antigen receptor)- and pre-TCR-mediated signaling, both in mature T-cells and during their development.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LAT	Other/Unknown	no		Linker_for_activat_Tcells_prot

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
granulocyte	1
lymph node	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LAT	134	broad	marker	granulocyte, lymph node, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LAT	977

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LAT	O43561	59.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TCR signaling	1	496.5×	0.006	LAT
DAP12 signaling	1	368.4×	0.006	LAT
FCERI mediated Ca+2 mobilization	1	356.9×	0.006	LAT
Generation of second messenger molecules	1	346.1×	0.006	LAT
FCERI mediated MAPK activation	1	346.1×	0.006	LAT
GPVI-mediated activation cascade	1	308.6×	0.006	LAT
Fc epsilon receptor (FCERI) signaling	1	271.9×	0.006	LAT
Platelet activation, signaling and aggregation	1	105.7×	0.014	LAT
RAF/MAP kinase cascade	1	61.1×	0.022	LAT
Hemostasis	1	36.0×	0.033	LAT
Adaptive Immune System	1	29.8×	0.037	LAT
Immune System	1	13.0×	0.077	LAT

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
membrane raft distribution	1	5617.3×	0.003	LAT
lymphocyte homeostasis	1	1872.4×	0.003	LAT
regulation of T cell activation	1	1872.4×	0.003	LAT
positive regulation of protein kinase activity	1	674.1×	0.005	LAT
mast cell degranulation	1	624.1×	0.005	LAT
T cell activation	1	259.3×	0.010	LAT
Ras protein signal transduction	1	205.5×	0.011	LAT
calcium-mediated signaling	1	183.2×	0.011	LAT
integrin-mediated signaling pathway	1	160.5×	0.011	LAT
T cell receptor signaling pathway	1	151.8×	0.011	LAT
adaptive immune response	1	84.3×	0.015	LAT
positive regulation of MAPK cascade	1	80.6×	0.015	LAT
gene expression	1	79.9×	0.015	LAT
immune response	1	47.1×	0.024	LAT
intracellular signal transduction	1	38.1×	0.027	LAT
inflammatory response	1	37.7×	0.027	LAT

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LAT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
LAT	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	LAT

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
LAT	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.