ERBIN

protein-coding

erbb2 interacting protein, the group of PDZ domain containing

Gene summary

This gene is a member of the leucine-rich repeat and PDZ domain (LAP) family. The encoded protein contains 17 leucine-rich repeats and one PDZ domain. It binds to the unphosphorylated form of the ERBB2 protein and regulates ERBB2 function and localization. It has also been shown to affect the Ras signaling pathway by disrupting Ras-Raf interaction. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

Previous symbols:

ERBB2IP

MANE transcript

NM_001253697.2

Inheritance

ClinVar variants

U:589B:219

Top phenotype

ERBIN-related disorder

gnomAD constraint

pLI —, LoF o/e 0.18

Max pathogenic AF

—

Genomic locus

chr5:65,883,128-66,082,546

External References & Databases

Ensembl (ENSG00000112851)

Transcript & Mutation Effects

hg38 • Region Span ~199.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

combined immunodeficiencyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0015131

Submitter: PanelApp Australia

autosomal dominant combined immunodeficiency due to ERBIN deficiencyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0958120

Submitter: ClinGen

ERBIN was first reported in relation to autosomal dominant combined immunodeficiency due to ERBIN deficiency in 2017 (Lyons et al., PMID: 28126831). Two missense variants reported in 2 probands in 2 publications are included in this curation (PMID: 28126831, 39836844). One variant, c.1588G>T (p.Asp530Tyr), segregated with disease in a family. This variant is present in population databases at a higher frequency than expected for rare disease. The condition is characterized by elevated IgE, eosinophilic esophagitis, joint hypermobility, and vascular abnormalities. The mechanism of pathogenicity appears to be loss of function. This gene-disease association is supported by protein interactions and functional assays. ERBIN forms a complex with activated STAT3 and SMAD2/3 (PMID: 28126831). STAT3 and SMAD2/3 have been previously established to be definitely associated with diseases with phenotypes overlapping that of ERBIN deficiency: hyper IgE syndrome and familial thoracic aortic aneurysm and aortic dissection. Normally this complex negatively regulates TGF-β activity, but in patient cells ERBIN fails to sequester SMAD2/3 in the cytoplasm, upregulating TGF-β signaling (PMID: 28126831). TGF-β signaling is critical for controlling human allergic disease. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen SCID/CID GCEP on the meeting date February 20, 2025 (SOP Version 11).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ERBIN variants in ClinVar

5 Conditions Cataloged

not providedTotal: 949

ERBIN-related disorderTotal: 83

not specifiedTotal: 47

Prostate cancerTotal: 1

Amelia cleft lip palate hydrocephalus iris colobomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001253697.2. 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			6 clinvar	192 clinvar	3 clinvar	201
missense			548 clinvar	18 clinvar	6 clinvar	572
nonsense			10 clinvar			10
start loss						0
frameshift			14 clinvar			14
splice donor/acceptor (+/-2bp)			11 clinvar			11
Total	0	0	589	210	9	808

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 89 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001253697.2	RefSeq	NP_001240626.1	24	MANE Select
ENST00000284037.10	Ensembl	ENSP00000284037.4	24	MANE Select
NM_001006600.3	RefSeq	NP_001006600.1	22	Standard
NM_001253698.2	RefSeq	NP_001240627.1	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

NOD-like receptor signaling pathway - Homo sapiens (human)
Nucleotide-binding Oligomerization Domain (NOD) pathway
NLR Proteins
Pathways Affected in Adenoid Cystic Carcinoma
Signal Transduction

Biological Process

protein targeting
cell adhesion
signal transduction
epidermal growth factor receptor signaling pathway
integrin-mediated signaling pathway

Molecular Function

signaling receptor binding
ErbB-2 class receptor binding
structural constituent of cytoskeleton
protein binding

Cellular Component

basement membrane
nucleus
cytoplasm
plasma membrane
basal plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000506030
Coding exons: 24
Length: 156075
Individuals with no LoFs: 125723
Homozygous LoFs: 0
Heterozygous LoFs: 25
Defined: 125748
p: 0.0000994

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.892	636	703	0.905	0.0000335	9392
Missense (PolyPhen)		224	286.54	0.78175		3912
Synonymous	0.0452	241	242	0.996	0.0000115	2613
Loss of Function	6.30	12	68.1	0.176	0.00000384	858

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.000034	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.00010	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as an adapter for the receptor ERBB2, in epithelia. By binding the unphosphorylated 'Tyr-1248' of receptor ERBB2, it may contribute to stabilize this unphosphorylated state (PubMed:16203728). Inhibits NOD2-dependent NF-kappa-B signaling and proinflammatory cytokine secretion (PubMed:16203728). {ECO:0000269|PubMed:10878805, ECO:0000269|PubMed:16203728}.;

Recessive Scores

pRec: 0.109

Intolerance Scores

RVIS EVS: 1.39
RVIS percentile EVS: 94.64

Essentials

Essential (gene trap): K