IGLL1

protein-coding

immunoglobulin lambda like polypeptide 1, the group of CD molecules|C1-set domain containing

Gene summary

The preB cell receptor is found on the surface of proB and preB cells, where it is involved in transduction of signals for cellular proliferation, differentiation from the proB cell to the preB cell stage, allelic exclusion at the Ig heavy chain gene locus, and promotion of Ig light chain gene rearrangements. The preB cell receptor is composed of a membrane-bound Ig mu heavy chain in association with a heterodimeric surrogate light chain. This gene encodes one of the surrogate light chain subunits and is a member of the immunoglobulin gene superfamily. This gene does not undergo rearrangement. Mutations in this gene can result in B cell deficiency and agammaglobulinemia, an autosomal recessive disease in which few or no gamma globulins or antibodies are made. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

IGLL

MANE transcript

NM_020070.4

Inheritance

AR, AD

ClinVar variants

P:1U:142B:91

Top phenotype

Agammaglobulinemia 2, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.69

Max pathogenic AF

—

Genomic locus

chr22:23,573,125-23,580,302

External References & Databases

Ensembl (ENSG00000128322)

Transcript & Mutation Effects

hg38 • Region Span ~7.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

agammaglobulinemia 2, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013287

Submitter: PanelApp Australia

agammaglobulinemia 2, autosomal recessiveLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0013287

Submitter: Labcorp Genetics (formerly Invitae)

agammaglobulinemia 2, autosomal recessiveLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013287

Submitter: Ambry Genetics

agammaglobulinemia 2, autosomal recessiveMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013287

Submitter: ClinGen

IGLL1 was first reported in relation to autosomal recessive agammaglobulinemia 2 in 1998 (Minegishi Y, et al., 1998, PMID: 9419212). IGLL1 encodes the omega polypeptide chain which associates with the Ig mu chain to form a molecular complex on the surface of pre-B cells. This complex presumably regulates Ig gene rearrangements in the early steps of B-cell differentiation. Biallelic variation in this gene thus results in B cell deficiency and agammaglobulinemia. This gene-disease relationship is supported by both genetic and experimental evidence. Three variants (nonsense, missense, and frameshift) have been reported in five probands (PMIDs: 25502423, 19302039, 27576013, 9419212, and 33178177) and one additional affected family member (PMID: 25502423). A role in disease is supported by the expression of IGLL1 in the relevant tissue of bone marrow, specifically enriched in naïve B-cells (PMID: 2501791) and by an IGLL1 deficient mouse model which recapitulates the block in B cell development seen in patients (PMID: 1591779). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

autosomal agammaglobulinemiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011096

Submitter: Orphanet

Clinical Genomic Database (CGD)

Agammaglobulinemia 2, autosomal recessiveAR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Antiinfectious prophylaxis (including with administration of IVIG) and early and aggressive treatment of infections may be beneficial

Refs: 9419212; 10077633; 10590911

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IGLL1 variants in ClinVar

4 Conditions Cataloged

Agammaglobulinemia 2, autosomal recessiveTotal: 233

not specifiedTotal: 76

not providedTotal: 51

IGLL1-related conditionTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020070.4. 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 clinvar	67 clinvar	6 clinvar	75
missense			119 clinvar	17 clinvar	1 clinvar	137
nonsense			5 clinvar			5
start loss						0
frameshift		1 clinvar	16 clinvar			17
splice donor/acceptor (+/-2bp)						0
Total	0	1	142	84	7	234

Highest pathogenic variant AF is 0.0013078329

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020070.4	RefSeq	NP_064455.1	3	MANE Select
ENST00000330377.3	Ensembl	ENSP00000329312.2	3	MANE Select
NM_001369906.1	RefSeq	NP_001356835.1	3	Standard
NM_152855.3	RefSeq	NP_690594.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Primary immunodeficiency - Homo sapiens (human)
Cell surface interactions at the vascular wall
Hemostasis

Biological Process

phagocytosis, recognition
phagocytosis, engulfment
immune response
complement activation, classical pathway
defense response to bacterium

Molecular Function

antigen binding
immunoglobulin receptor binding

Cellular Component

extracellular region
external side of plasma membrane
membrane
immunoglobulin complex, circulating

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000330377
Coding exons: 3
Length: 7184
Individuals with no LoFs: 125492
Homozygous LoFs: 1
Heterozygous LoFs: 247
Defined: 125740
p: 0.000987

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.298	134	125	1.07	0.00000793	1326
Missense (PolyPhen)		23	21.311	1.0793		281
Synonymous	-1.52	73	58.2	1.25	0.00000419	452
Loss of Function	0.596	3	4.34	0.691	1.87e-7	42

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0.0018	0.0018	notable
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0018	0.0018	notable
South Asian	0.00029	0.00026	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Critical for B-cell development. {ECO:0000269|PubMed:9419212}.;

Recessive Scores

pRec: 0.285

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0989

Gene Damage Prediction

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