MIB1

Chr 18AD

MIB E3 ubiquitin protein ligase 1

Also known as: DIP-1, DIP1, LVNC7, MIB, ZZANK2, ZZZ6

NCBI Gene: 57534 ENSG00000101752 UniProt: Q86YT6 OMIM: 608677

The MIB1 protein functions as an E3 ubiquitin ligase that positively regulates Notch signaling by ubiquitinating Notch receptors to facilitate their endocytosis, and is also involved in regulating apoptosis and primary cilium formation. Mutations cause left ventricular noncompaction, a cardiomyopathy characterized by prominent trabeculations and deep intertrabecular recesses in the left ventricle. This condition follows autosomal dominant inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Left ventricular noncompaction 7MIM #615092

Clinical highlights

Gene–disease validity (ClinGen)

Limited · dilated cardiomyopathy · AD · ClinGen 2024

not for standalone diagnostic reporting

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.97

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

1.97LOEUF

pLI 0.000

Z-score -5.81

OE 1.83 (1.54–1.97)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

3.21Z-score

OE missense 0.62 (0.56–0.67)

343 obs / 556.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?1.83 (1.54–1.97)

0≤0.351.4

Missense OE?0.62 (0.56–0.67)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 105 / 57.5Missense obs/exp: 343 / 556.1Syn Z: -0.41

Background carrier burden — how many people carry a rare variant somewhere in MIB1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

1,032 rare PASS variants

Rare truncating (LoF)

1 in 280

735 rare PASS variants

Rare synonymous (reference)

1 in 100

470 rare PASS variants

Rare missense and truncating variants are carried at similar rates in MIB1; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 140	1 in 280
South Asian	~43k	1 in 110	1 in 180
Remaining (unassigned)	~30k	1 in 140	1 in 370
European (Finnish)	~27k	1 in 260	1 in 280
Admixed American	~22k	1 in 120	1 in 220
African / African American	~21k	1 in 110	1 in 370
East Asian	~20k	1 in 100	1 in 330
Ashkenazi Jewish	~13k	1 in 720	1 in 380
Middle Eastern	~2,884	1 in 170	1 in 290

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 16 of 21 coding exons well covered in gnomAD exomes; exons 5, 12, 13, 14, 20 marginal. Genomes: all 21.? see exons ↓