Mendeliome
Gene: MIB1 Amber List (moderate evidence)I don't know
Luxan 2013 (PMID: 23314057):
- V943F, seg with LVNC in 1 fam, (gnomADv2: 43 hets).
- R530X, seg with LVNC in 1 fam, (gv2: 13 hets).
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.
DCM-association = none by Clingen (9/4/2020), ref Luxan 2013 and other pprs, and mentioned gnomAD had too many LoF variants.
De Ligt 2012 (PMID: 23033978): de novo R174H (gnomADv2: 7 hets), indvl with severe ID who also has a de novo R47* in WAC (an AD ID gene with LoF established, variant is P in ClinVar), no other pt-specific pheno provided.
Kaplanis 2021 (PMID: 33057194): Developmental disorders paper.
- 2 missense variants, de novo: 18-19383967-G-A (p.Glu491Lys, gv2 1 het, gv3 absent), 18-19378124-C-T (Thr391Ile, gv2v3 absent, DDD, de novo, no mention of heart pheno).
- Of 6 PTVs, 4 had at least 10 hets each in gnomADv2.Created: 16 Dec 2021, 5:02 a.m. | Last Modified: 16 Dec 2021, 5:03 a.m.
Panel Version: 0.10257
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications
I don't know
Comment when marking as ready: RED for LVNC/cardiomyopathy. Amber for congenital heart disease.Created: 26 Mar 2021, 9:45 a.m. | Last Modified: 16 Dec 2021, 5:56 a.m.
Panel Version: 0.10260
Evidence is mostly experimental: The MIB1 mRNA and protein are expressed in the heart (Jin et al, 2002, PMID: 12351649). In the mouse Luxán G et al used in situ hybridization to show that Mib1 is expressed in mouse endocardium and myocardium at embryonic day 9.5 (Luxan et al,2013, PMID: 23314057). Two cardiac specific Mib1 knock-out mouse models both had dilated heart with a thin compact myocardium and large, noncompacted trabeculae protruding toward the ventricular lumen. For the first model Nkx2.5-cre mice were used to knock out the Mib1flox/flox allele. In these mice cre is active in the endocardium and myocardium from E7.5 onward and they died at birth from valve dysfunction. For the second model cTnT-cre (also known as Tnnt2-cre) mice were used. In these mice cre is active from E8.0 onward in the myocardium. In addition, Mib1flox; cTnT-cre mice survive but showed a dilated heart with noncompaction and a significantly reduced ejection fraction (Luxan et al, 2013, PMID: 23314057, Captur et al, 2016, PMID: 27020702).
Variants in PMID 23314057 have a relatively high population frequency in gnomad, out of keeping for a Mendelian disorder.Created: 26 Mar 2021, 9:44 a.m. | Last Modified: 26 Mar 2021, 9:44 a.m.
Panel Version: 0.6897
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Left ventricular noncompaction 7, MIM# 615092; cardiomyopathy
Publications
Comment on phenotypes: Established congenital cardiac disease gene.
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).Created: 2 Nov 2020, 11:52 p.m. | Last Modified: 2 Nov 2020, 11:52 p.m.
Panel Version: 0.5286
Publications for gene: MIB1 were set to 23314057; 30322850
Gene: mib1 has been classified as Amber List (Moderate Evidence).
Gene: mib1 has been classified as Green List (High Evidence).
Phenotypes for gene: MIB1 were changed from Left ventricular noncompaction 7 MIM#615092 to Left ventricular noncompaction 7 MIM#615092; cardiomyopathy; congenital heart disease
Publications for gene: MIB1 were set to
Phenotypes for gene: MIB1 were changed from to Left ventricular noncompaction 7 MIM#615092
Mode of inheritance for gene: MIB1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
gene: MIB1 was added gene: MIB1 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: MIB1 was set to Unknown
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.