CD40LG

protein-coding

CD40 ligand, the group of CD molecules|Tumor necrosis factor superfamily

Gene summary

The protein encoded by this gene is expressed on the surface of T cells. It regulates B cell function by engaging CD40 on the B cell surface. A defect in this gene results in an inability to undergo immunoglobulin class switch and is associated with hyper-IgM syndrome. [provided by RefSeq, Jul 2008]

Previous symbols:

HIGM1
IMD3
TNFSF5

MANE transcript

NM_000074.3

Inheritance

ClinVar variants

P:110U:93B:76

Top phenotype

Immunodeficiency, with hyper-IgM, type 1

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chrX:136,648,158-136,660,390

External References & Databases

Ensembl (ENSG00000102245)

Transcript & Mutation Effects

hg38 • Region Span ~12.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyper-IgM syndrome type 1DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010626

Submitter: Ambry Genetics

hyper-IgM syndrome type 1STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010626

Submitter: Labcorp Genetics (formerly Invitae)

hyper-IgM syndrome type 1SUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010626

Submitter: Orphanet

hyper-IgM syndrome type 1DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010626

Submitter: ClinGen

CD40LG was first reported in relation to X-linked hyper IgM (HIGM) syndrome in 1993 by multiple groups independently (Korthauer et al., PMID: 7679206; DiSanto et al., PMID: 8094231; Allen et al., PMID: 7679801; Aruffo et al., PMID: 7678782). CD40LG encodes the protein CD40 ligand, a transmembrane molecule found on T cells. HIGM syndrome is a primary immunodeficiency disorder caused by defective immunoglobulin class switch recombination. It is characterized by decreased levels of certain immunoglobulins including IgG, IgA, and IgE with normal or increased levels of IgM. These deficiencies increase susceptibility to severe and opportunistic infections that can be recurrent and life threatening. HIGM syndrome due to CD40 ligand deficiency occurs almost exclusively in males. Heterozygous females typically are asymptomatic with normal levels of immunoglobulins (PMID: 7518839), although rare cases of clinically affected female carriers have been reported when X chromosome inactivation is skewed (PMID: 9933119, 16311023). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 16 variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, complex rearrangement, etc.) have been reported in at least 16 probands in 7 publications (PMID: 7679206, 8094231, 7679801, 7678782, 9933119, 15358621, 15997875). Many are loss of function variants, establishing this as the molecular mechanism of the condition. This gene-disease association is supported by expression studies, in vitro functional assays, animal models, and rescue assays (PMID: 1280226, 7964465, 7882172, 26903548, 29847792, 33475257, 21285457). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence (18 pts.) has been reached. In summary, CD40LG is definitively associated with X-linked recessive hyper IgM syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID/CID Working Group on DATE (SOP Version 8).

Clinical Genomic Database (CGD)

Immunodeficiency, with hyper-IgM, type 1XL

Manifestation: Allergy/Immunology/Infectious; Hematologic; Oncologic

Intervention: Allergy/Immunology/Infectious; Oncologic

Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Individuals have been described as being at increased risk of malignancy, and awareness may allow early detection and management; BMT has been reported

Refs: 7679801; 7678782; 7542361; 9255191; 10228294; 10931436; 10655530; 17296845; 20301576; 23010537; 22322937

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CD40LG variants in ClinVar

7 Conditions Cataloged

Hyper-IgM syndrome type 1Total: 276

not providedTotal: 47

not specifiedTotal: 25

Inborn genetic diseasesTotal: 17

CD40LG-related disorderTotal: 9

Common variable immunodeficiencyTotal: 2

Hyperimmunoglobulin M syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000074.3. 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			7 clinvar	49 clinvar	8 clinvar	64
missense	10 clinvar	25 clinvar	83 clinvar	11 clinvar	8 clinvar	137
nonsense	18 clinvar	7 clinvar	1 clinvar			26
start loss						0
frameshift	28 clinvar	7 clinvar	1 clinvar			36
splice donor/acceptor (+/-2bp)	13 clinvar	2 clinvar	1 clinvar			16
Total	69	41	93	60	16	279

Highest pathogenic variant AF is 0.000008951029

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000074.3	RefSeq	NP_000065.1	5	MANE Select
ENST00000370629.7	Ensembl	ENSP00000359663.2	5	MANE Select
ENST00000370628.2	Ensembl	ENSP00000359662.2	4	Standard
ENST00000370628.3	Ensembl	ENSP00000359662.2	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Primary immunodeficiency - Homo sapiens (human)
Cell adhesion molecules (CAMs) - Homo sapiens (human)
T cell receptor signaling pathway - Homo sapiens (human)
Allograft rejection - Homo sapiens (human)
Viral myocarditis - Homo sapiens (human)

Biological Process

inflammatory response
leukocyte cell-cell adhesion
activation of JUN kinase activity
regulation of signaling receptor activity
platelet activation

Molecular Function

cytokine activity
tumor necrosis factor receptor binding
CD40 receptor binding
protein binding

Cellular Component

extracellular space
plasma membrane
integral component of plasma membrane
external side of plasma membrane
cell surface

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000370629
Coding exons: 5
Length: 12198
Individuals with no LoFs: 124699
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 124701
p: 0.00000802

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.30	61	97.1	0.628	0.00000715	1730
Missense (PolyPhen)		7	23.349	0.2998		433
Synonymous	1.03	32	40.3	0.794	0.00000347	480
Loss of Function	2.39	1	8.52	0.117	6.12e-7	152

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000025	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cytokine that binds to CD40/TNFRSF5 (PubMed:1280226). Costimulates T-cell proliferation and cytokine production. Its cross-linking on T-cells generates a costimulatory signal which enhances the production of IL4 and IL10 in conjunction with the TCR/CD3 ligation and CD28 costimulation (PubMed:8617933). Induces the activation of NF-kappa-B and kinases MAPK8 and PAK2 in T- cells. Induces tyrosine phosphorylation of isoform 3 of CD28 (PubMed:15067037). Mediates B-cell proliferation in the absence of co-stimulus as well as IgE production in the presence of IL4. Involved in immunoglobulin class switching (By similarity). {ECO:0000250|UniProtKB:P27548, ECO:0000269|PubMed:1280226, ECO:0000269|PubMed:15067037, ECO:0000269|PubMed:8617933}.;
Disease: DISEASE: Immunodeficiency with hyper-IgM, type 1 (HIGM1) [MIM:308230]: Immunoglobulin isotype switch defect characterized by elevated concentrations of serum IgM and decreased amounts of all other isotypes. Affected males present at an early age (usually within the first year of life) recurrent bacterial and opportunistic infections, including Pneumocystis carinii pneumonia and intractable diarrhea due to cryptosporidium infection. Despite substitution treatment with intravenous immunoglobulin, the overall prognosis is rather poor, with a death rate of about 10% before adolescence. {ECO:0000269|PubMed:26545377, ECO:0000269|PubMed:7532185, ECO:0000269|PubMed:7678782, ECO:0000269|PubMed:7679206, ECO:0000269|PubMed:7679801, ECO:0000269|PubMed:7717401, ECO:0000269|PubMed:8094231, ECO:0000269|PubMed:8550833, ECO:0000269|PubMed:8889581, ECO:0000269|PubMed:9150729, ECO:0000269|PubMed:9746782}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.761

Intolerance Scores

RVIS EVS: -0.03
RVIS percentile EVS: 51.4

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.642

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium