Fetal anomalies
Gene: MIB1 Red List (low evidence)Red List (low evidence)
De Ligt 2012 (PMID: 23033978): 1x individual with ID has de novo R174H (v4: 54 hets), also has a de novo pathogenic variant (R47*) in WAC
Luxan 2013 (PMID: 23314057): 2x families with LVNC (V943F, gnomAD v4: 159 hets, 1 hom and R530X, v4: 64 hets, 0 homs)
Kaplanis 2021 (PMID: 33057194): 2x rare de novo missense and 6x PTVs in individuals with developmental disorder, but many NMD variants in gnomAD v4 (pLI = 0), 11x with over 50 hets (highest 109 hets)
Li 2018 (PMID: 30322850): 3x CHD patients with missense variants (absent/rare gnomAD v4) and 1x NMD variant; overexpression of wt or mutant in zebrafish all resulted in dysmorphic phenotype, therefore not informative.
Tessler 2023 (PMID: 37405741) - Individuals with nonsyndromic bicuspid aortic valve (called rare due to het counts in gnomAD v2):
• Variants reported include R97* (v4: 80 hets), D380N (v4 absent), I591F (v4: 276 hets), K735R (v4: 8 hets), R769* (v4: 56 hets), R804Q (v4: 646 hets), V943F (v4: 159 hets, 1 hom), R1001* (v4: 33 hets)
• Mouse models het and hom for K735R were unaffected (normal heart morphology); mice het for V943F also unaffected
• However, combination of Mib1 het variants with Notch1 het LoF variant (green in cardiac panels; LoF established) showed BAV and associated defects with penetrance of 44%
Pineiro-Sabaris 2024 (PMID: 39057643) - Mouse models (K735R, V943F, R530X) show no significant change in BAV prevalence compared to wildtype
ClinGen Review: DCM-association = no known disease relationship (9/4/2020)
MIB1 is NOT constrained for LoF (DECIPHER/gnomAD v4). All variants classified as LP in ClinVar come from a single lab with no supporting evidence of pathogenicity provided.Created: 30 Jun 2025, 1:01 a.m. | Last Modified: 30 Jun 2025, 1:01 a.m.
Panel Version: 1.372
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
I don't know
Last reviewed March and Dec 2021 - no additional evidence
Li 2018 (PMID: 30322850):
- in 4 CHD patients: p.Q237H (gv2v3 absent), p.W271G (gv2v3 absent), p.S520R (v2 5 hets) and p.T312Kfs*55 (NMD-pred, absent but many comparables in gnomAD).
- HEK293T cells transfection studies showed: T312Kfs*55 and W271G strongly impaired MIB1 function on substrate ubiquitination, while Q237H and S520R had slight or no obvious changes. Interaction between MIB1 and JAG1 is severely interrupted by p.T312Kfs*55 and p.W271G, but not really in the other 2 missense.
- Overexpression of wt or mutant in zebrafish all resulted in dysmorphic pheno, therefore not informative.
PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 11 de novo variants (1 frameshift, 2 missense, 2 splice acceptor, 1 splice donor, 5 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Expert list, LiteratureCreated: 20 Dec 2021, 1:35 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Congenital heart disease
Publications
Gene: mib1 has been classified as Red List (Low Evidence).
Gene: mib1 has been classified as Amber List (Moderate Evidence).
Gene: mib1 has been classified as Amber List (Moderate Evidence).
gene: MIB1 was added gene: MIB1 was added to Fetal anomalies. Sources: Expert list,Literature Mode of inheritance for gene: MIB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MIB1 were set to 33057194 Phenotypes for gene: MIB1 were set to Congenital heart disease Review for gene: MIB1 was set to AMBER
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.