MIB1

protein-coding

MIB E3 ubiquitin protein ligase 1, the group of Zinc fingers ZZ-type|Ankyrin repeat domain containing|MicroRNA protein coding host genes|Ring finger proteins

Gene summary

This gene encodes a protein containing multiple ankyrin repeats and RING finger domains that functions as an E3 ubiquitin ligase. The encoded protein positively regulates Notch signaling by ubiquitinating the Notch receptors, thereby facilitating their endocytosis. This protein may also promote the ubiquitination and degradation of death-associated protein kinase 1 (DAPK1). [provided by RefSeq, Jun 2013]

MANE transcript

NM_020774.4

Inheritance

ClinVar variants

P:33U:379B:197

Top phenotype

Left ventricular noncompaction 7

gnomAD constraint

pLI —, LoF o/e 1.83

Max pathogenic AF

—

Genomic locus

chr18:21,704,957-21,870,953

External References & Databases

Ensembl (ENSG00000101752)

Transcript & Mutation Effects

hg38 • Region Span ~166.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

left ventricular noncompactionSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018901

Submitter: Orphanet

dilated cardiomyopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: ClinGen

MIB1 was originally evaluated for DCM by the ClinGen DCM GCEP on November 8, 2019. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on October 4, 2024. As a result, the classification changed from no known disease relationship to limited. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. MIB1 was first reported in relation to autosomal dominant dilated cardiomyopathy in 2013 (Luxan et al. PMID: 23314057). Human genetic evidence supporting this gene-disease relationship includes case-level data. Four variants (2 missense, 1 splice site, 1 truncating) have been reported in humans in 2 studies (Luxan et al. PMID 23314057, Hazebroek et al. PMID: 29540472). Segregation was demonstrated in 2 families in Luxan et al. although, interestingly, most affected relatives had isolated left ventricular hypertrabeculation, and it was only the probands from both families that had contractile dysfunction. Functional evidence was demonstrated for these 2 variants. Importantly, this paper did not exclude truncating TTN variants. Further, this gene appears to be tolerant of loss of function variants. Hazebroek et al. identified two MIB1 variants in people with non-dilated hypokinetic cardiomyopathy, without segregation or functional evidence. None of these variants were scored in the last curation due to insufficient DCM phenotype. While there have been no new publications demonstrating an association between MIB1 and DCM since the last curation, on re-evaluation of the genetic data, the 2024 working group thought the described phenotypes were reasonable and a small number of points were warranted for this genetic evidence. This gene disease association is supported by a mouse animal model (Luxan et al. PMID 23314057, Captur et al. PMID: 27020702), and expression studies (Luxan et al. PMID 23314057, Jin et al. PMID: 12351649). In summary, despite no new evidence, on re-curation of the genetic evidence for MIB1 and AD DCM, the expert panel have upgraded this gene-disease classification to Limited. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 4 October, 2024 (SOP Version 10).

isolated cleft palateNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0007336

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

left ventricular noncompaction 7LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014042

Submitter: Labcorp Genetics (formerly Invitae)

left ventricular noncompaction 7MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014042

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Left ventricular noncompaction 7AD

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: Left ventricular noncompaction may manifest as depressed systolic function, with potential complications including arrhythmias, systemic embolism, heart failure and sudden death, and surveillance (eg, with echocardiogram and electrocardiogram) may allow early diagnosis and treatment

Refs: 23314057

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MIB1 variants in ClinVar

9 Conditions Cataloged

Inborn genetic diseasesTotal: 434

not providedTotal: 216

not specifiedTotal: 53

Left ventricular noncompaction 7Total: 52

MIB1-related disorderTotal: 37

Primary dilated cardiomyopathyTotal: 1

Hypercholesterolemia, familial, 1Total: 1

Autism spectrum disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020774.4. 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			3 clinvar	191 clinvar		194
missense		2 clinvar	309 clinvar	5 clinvar		316
nonsense	1 clinvar	9 clinvar	25 clinvar	1 clinvar		36
start loss						0
frameshift		16 clinvar	31 clinvar			47
splice donor/acceptor (+/-2bp)		5 clinvar	11 clinvar			16
Total	1	32	379	197	0	609

Highest pathogenic variant AF is 0.00010037644

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020774.4	RefSeq	NP_065825.1	21	MANE Select
ENST00000261537.7	Ensembl	ENSP00000261537.6	21	MANE Select
ENST00000864012.1	Ensembl	ENSP00000534071.1	20	Standard
ENST00000864012.2	Ensembl	ENSP00000534071.1	20	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
mib1	Danio rerio	Structure: retinal ganglion cell Quality: dead abnormal

Gene / Model

Organism

Observed Phenotype

mib1

Danio rerio

Structure: retinal ganglion cell

Quality: dead

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

NOTCH-Ncore
Disease
Signal Transduction
Signaling by NOTCH1
Signaling by NOTCH2

Biological Process

blood vessel development
in utero embryonic development
somitogenesis
neural tube formation
heart looping

Molecular Function

ubiquitin-protein transferase activity
protein binding
zinc ion binding

Cellular Component

cytoplasm
centrosome
cytosol
plasma membrane
postsynaptic density

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261537
Coding exons: 21
Length: 166001
Individuals with no LoFs: 125339
Homozygous LoFs: 0
Heterozygous LoFs: 409
Defined: 125748
p: 0.00163

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.21	343	556	0.617	0.0000285	6612
Missense (PolyPhen)		87	167.28	0.5201		1899
Synonymous	-0.413	199	192	1.04	0.00000949	1921
Loss of Function	-5.81	105	57.5	1.83	0.00000350	615

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0017	0.0017	notable
Latino/Admixed American	0.0018	0.0018	notable
Ashkenazi Jewish	0.0019	0.0019	notable
East Asian	0.0014	0.0014	notable
Finnish	0.0014	0.0014	notable
European (Non-Finnish)	0.0016	0.0016	notable
South Asian	0.0019	0.0019	notable
Other	0.0020	0.0020	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins. Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors. Probably mediates ubiquitination and subsequent proteasomal degradation of DAPK1, thereby antagonizing anti-apoptotic effects of DAPK1 to promote TNF- induced apoptosis (By similarity). Involved in ubiquitination of centriolar satellite CEP131, CEP290 and PCM1 proteins and hence inhibits primary cilium formation in proliferating cells. Mediates 'Lys-63'-linked polyubiquitination of TBK1, which probably participates in kinase activation. {ECO:0000250, ECO:0000269|PubMed:24121310}.;
Disease: DISEASE: Left ventricular non-compaction 7 (LVNC7) [MIM:615092]: A form of left ventricular non-compaction, a cardiomyopathy due to myocardial morphogenesis arrest and characterized by a hypertrophic left ventricle, a severely thickened 2-layered myocardium, numerous prominent trabeculations, deep intertrabecular recesses, and poor systolic function. Clinical manifestations are variable. Some affected individuals experience no symptoms at all, others develop heart failure. In some cases, left ventricular non-compaction is associated with other congenital heart anomalies. LVNC7 is an autosomal dominant condition. {ECO:0000269|PubMed:23314057}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.290

Intolerance Scores

LoFtool: 0.882
RVIS EVS: -1.42
RVIS percentile EVS: 4.1

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.960

Gene Damage Prediction

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