severe combined immunodeficiency due to LCK deficiency

Summary

severe combined immunodeficiency due to LCK deficiency (MONDO:0014334) is a disease caused by LCK (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LCK (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 293

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	severe combined immunodeficiency due to LCK deficiency
Mondo ID	MONDO:0014334
OMIM	615758
Orphanet	280142
DOID	DOID:0111937
ICD-11	999642330
UMLS	C4014233
MedGen	862670
GARD	0017288
Is cancer (heuristic)	no

Also known as: IMD22 · immunodeficiency 22 · immunodeficiency type 22 · SCID due to LCK deficiency · SCID due to lymphocyte-specific protein tyrosine kinase deficiency · severe combined immunodeficiency due to lymphocyte-specific protein tyrosine kinase deficiency

Data availability: 293 ClinVar variants · 5 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 LCK deficiency

Related subtypes (15): severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, short-limb skeletal dysplasia with severe combined immunodeficiency, combined immunodeficiency with skin granulomas, reticular dysgenesis, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, severe combined immunodeficiency due to DCLRE1C deficiency, Omenn syndrome, DNA ligase IV deficiency, neutrophil immunodeficiency syndrome, combined immunodeficiency due to partial RAG1 deficiency, Cernunnos-XLF deficiency, severe combined immunodeficiency due to DNA-PKcs deficiency, immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia, immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia, reticular dysgenesis-like severe combined immunodeficiency

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

293 retrieved; paginated sample, class counts are floors:

191 likely benign, 77 uncertain significance, 9 pathogenic, 8 likely pathogenic, 5 benign, 2 benign/likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1038789	NM_005356.5(LCK):c.415del (p.Arg139fs)	LCK	Pathogenic	criteria provided, single submitter
127135	NM_005356.5(LCK):c.1022T>C (p.Leu341Pro)	LCK	Pathogenic	no assertion criteria provided
1411689	NM_005356.5(LCK):c.477del (p.Ala160fs)	LCK	Pathogenic	criteria provided, single submitter
2041799	NM_005356.5(LCK):c.115C>T (p.Arg39Ter)	LCK	Pathogenic	criteria provided, single submitter
2858686	NM_005356.5(LCK):c.1126del (p.Thr375_Leu376insTer)	LCK	Pathogenic	criteria provided, single submitter
3064211	NM_005356.5(LCK):c.188-2A>G	LCK	Pathogenic	no assertion criteria provided
3064212	NM_005356.5(LCK):c.1393T>C (p.Cys465Arg)	LCK	Pathogenic	no assertion criteria provided
3064214	NM_005356.5(LCK):c.1318C>T (p.Pro440Ser)	LCK	Pathogenic	no assertion criteria provided
847660	NM_005356.5(LCK):c.1201A>T (p.Lys401Ter)	LCK	Pathogenic	criteria provided, single submitter
2068900	NM_005356.5(LCK):c.481+2T>G	LCK	Likely pathogenic	criteria provided, single submitter
3376436	NM_005356.5(LCK):c.1515C>A (p.Tyr505Ter)	LCK	Likely pathogenic	criteria provided, single submitter
3689457	NM_005356.5(LCK):c.785-1G>A	LCK	Likely pathogenic	criteria provided, single submitter
3779812	NM_005356.5(LCK):c.584dup (p.Arg196fs)	LCK	Likely pathogenic	criteria provided, single submitter
4723903	NM_005356.5(LCK):c.482-1G>A	LCK	Likely pathogenic	criteria provided, single submitter
4735122	NM_005356.5(LCK):c.1042-1G>T	LCK	Likely pathogenic	criteria provided, single submitter
4761675	NM_005356.5(LCK):c.481+1G>A	LCK	Likely pathogenic	criteria provided, single submitter
804376	NM_005356.5(LCK):c.1129dup (p.Ser377fs)	LCK	Likely pathogenic	criteria provided, single submitter
569666	NM_005356.5(LCK):c.601G>A (p.Gly201Ser)	LCK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1003637	NM_005356.5(LCK):c.1405C>A (p.Leu469Met)	LCK	Uncertain significance	criteria provided, single submitter
1018077	NM_005356.5(LCK):c.1292C>T (p.Thr431Met)	LCK	Uncertain significance	criteria provided, multiple submitters, no conflicts
1021516	NM_005356.5(LCK):c.343T>C (p.Phe115Leu)	LCK	Uncertain significance	criteria provided, multiple submitters, no conflicts
1025318	NM_005356.5(LCK):c.437A>G (p.Asn146Ser)	LCK	Uncertain significance	criteria provided, single submitter
1033244	NM_005356.5(LCK):c.1514A>G (p.Tyr505Cys)	LCK	Uncertain significance	criteria provided, single submitter
1034906	NM_005356.5(LCK):c.1501A>C (p.Thr501Pro)	LCK	Uncertain significance	criteria provided, single submitter
1036260	NM_005356.5(LCK):c.560A>G (p.Asp187Gly)	LCK	Uncertain significance	criteria provided, multiple submitters, no conflicts
1039527	NM_005356.5(LCK):c.104C>T (p.Thr35Met)	LCK	Uncertain significance	criteria provided, single submitter
1054739	NM_005356.5(LCK):c.1219A>G (p.Thr407Ala)	LCK	Uncertain significance	criteria provided, single submitter
1362283	NM_005356.5(LCK):c.587G>A (p.Arg196Gln)	LCK	Uncertain significance	criteria provided, single submitter
1370305	NM_005356.5(LCK):c.49A>G (p.Ile17Val)	LCK	Uncertain significance	criteria provided, single submitter
1405226	NM_005356.5(LCK):c.326G>T (p.Gly109Val)	LCK	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
LCK	Definitive	Autosomal recessive	severe combined immunodeficiency due to LCK deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LCK	Orphanet:280142	Combined immunodeficiency due to LCK 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
LCK	HGNC:6524	ENSG00000182866	P06239	Tyrosine-protein kinase Lck	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LCK	Tyrosine-protein kinase Lck	Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T-cells in the thymus and in the function of mature T-cells.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LCK	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom

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
granulocyte	1
lymph node	1
thymus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LCK	207	broad	marker	thymus, granulocyte, lymph node

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LCK	5,556

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LCK	P06239	57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 53. 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
FLT3 signaling through SRC family kinases	1	1631.4×	0.006	LCK
Nef and signal transduction	1	1268.9×	0.006	LCK
Nef Mediated CD4 Down-regulation	1	1268.9×	0.006	LCK
Signaling by KIT in disease	1	1142.0×	0.006	LCK
Interleukin-2 signaling	1	951.7×	0.006	LCK
PECAM1 interactions	1	878.5×	0.006	LCK
CD28 dependent Vav1 pathway	1	878.5×	0.006	LCK
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	1	634.4×	0.006	LCK
The role of Nef in HIV-1 replication and disease pathogenesis	1	634.4×	0.006	LCK
Translocation of ZAP-70 to Immunological synapse	1	634.4×	0.006	LCK
Interleukin-2 family signaling	1	634.4×	0.006	LCK
Regulation of KIT signaling	1	601.0×	0.006	LCK
Phosphorylation of CD3 and TCR zeta chains	1	543.8×	0.006	LCK
Co-inhibition by CTLA4	1	519.1×	0.006	LCK
Co-inhibition by PD-1	1	519.1×	0.006	LCK
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	1	519.1×	0.006	LCK
TCR signaling	1	496.5×	0.006	LCK
DAP12 interactions	1	475.8×	0.006	LCK
Regulation of T cell activation by CD28 family	1	423.0×	0.006	LCK
CD28 dependent PI3K/Akt signaling	1	393.8×	0.006	LCK
Co-stimulation by CD28	1	380.7×	0.006	LCK
PI3K/AKT Signaling in Cancer	1	368.4×	0.006	LCK
DAP12 signaling	1	368.4×	0.006	LCK
Generation of second messenger molecules	1	346.1×	0.006	LCK
FLT3 Signaling	1	346.1×	0.006	LCK
Host Interactions of HIV factors	1	335.9×	0.006	LCK
GPVI-mediated activation cascade	1	308.6×	0.006	LCK
RHOH GTPase cycle	1	308.6×	0.006	LCK
Negative regulation of the PI3K/AKT network	1	278.5×	0.007	LCK
Signaling by SCF-KIT	1	248.3×	0.007	LCK

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
regulation of lymphocyte activation	1	16852.0×	0.001	LCK
positive regulation of leukocyte cell-cell adhesion	1	5617.3×	0.002	LCK
CD27 signaling pathway	1	3370.4×	0.002	LCK
gamma-delta T cell differentiation	1	2106.5×	0.002	LCK
Fc-gamma receptor signaling pathway	1	1872.4×	0.002	LCK
positive regulation of gamma-delta T cell differentiation	1	1872.4×	0.002	LCK
regulation of regulatory T cell differentiation	1	1872.4×	0.002	LCK
positive regulation of heterotypic cell-cell adhesion	1	1296.3×	0.002	LCK
positive regulation of T cell receptor signaling pathway	1	766.0×	0.003	LCK
leukocyte migration	1	624.1×	0.004	LCK
positive regulation of intrinsic apoptotic signaling pathway	1	481.5×	0.004	LCK
positive regulation of T cell activation	1	443.5×	0.004	LCK
B cell receptor signaling pathway	1	401.2×	0.004	LCK
T cell differentiation	1	383.0×	0.004	LCK
T cell costimulation	1	374.5×	0.004	LCK
release of sequestered calcium ion into cytosol	1	343.9×	0.004	LCK
hemopoiesis	1	267.5×	0.005	LCK
platelet activation	1	267.5×	0.005	LCK
T cell activation	1	259.3×	0.005	LCK
cell surface receptor protein tyrosine kinase signaling pathway	1	173.7×	0.007	LCK
T cell receptor signaling pathway	1	151.8×	0.008	LCK
response to xenobiotic stimulus	1	69.1×	0.016	LCK
positive regulation of gene expression	1	38.7×	0.026	LCK
intracellular signal transduction	1	38.1×	0.026	LCK

Therapeutics

Drug target analysis

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

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

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
LCK	LEVODOPA

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LCK	126	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LEVODOPA	4	LCK
CISPLATIN	4	LCK
PONATINIB	4	LCK
AFATINIB	4	LCK
BACITRACIN	4	LCK
CARBIDOPA	4	LCK
GRAMICIDIN	4	LCK
INSULIN HUMAN	4	LCK
FEDRATINIB	4	LCK
TIVOZANIB	4	LCK
AXITINIB	4	LCK
SORAFENIB	4	LCK
DASATINIB ANHYDROUS	4	LCK
NERATINIB	4	LCK
INFIGRATINIB PHOSPHATE	4	LCK
INFIGRATINIB	4	LCK
IBRUTINIB	4	LCK
ENTRECTINIB	4	LCK
DABRAFENIB	4	LCK
PACRITINIB	4	LCK
TOFACITINIB CITRATE	4	LCK
AFATINIB DIMALEATE	4	LCK
CABOZANTINIB	4	LCK
DACOMITINIB ANHYDROUS	4	LCK
TOFACITINIB	4	LCK
CERITINIB	4	LCK
VANDETANIB	4	LCK
TRIBROMSALAN	4	LCK
NILOTINIB	4	LCK
BOSUTINIB	4	LCK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
LCK	1,393	Binding:1379, Functional:8, ADMET:5, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LCK	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
LCK	1,393

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

30 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.

Compound	Max phase	Cohort target (bioactivity)
LEVODOPA	4	LCK
CISPLATIN	4	LCK
PONATINIB	4	LCK
AFATINIB	4	LCK
BACITRACIN	4	LCK
CARBIDOPA	4	LCK
GRAMICIDIN	4	LCK
INSULIN HUMAN	4	LCK
FEDRATINIB	4	LCK
TIVOZANIB	4	LCK
AXITINIB	4	LCK
SORAFENIB	4	LCK
DASATINIB ANHYDROUS	4	LCK
NERATINIB	4	LCK
INFIGRATINIB PHOSPHATE	4	LCK
INFIGRATINIB	4	LCK
IBRUTINIB	4	LCK
ENTRECTINIB	4	LCK
DABRAFENIB	4	LCK
PACRITINIB	4	LCK
TOFACITINIB CITRATE	4	LCK
AFATINIB DIMALEATE	4	LCK
CABOZANTINIB	4	LCK
DACOMITINIB ANHYDROUS	4	LCK
TOFACITINIB	4	LCK
CERITINIB	4	LCK
VANDETANIB	4	LCK
TRIBROMSALAN	4	LCK
NILOTINIB	4	LCK
BOSUTINIB	4	LCK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	LCK
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.