Intellectual disability - microarray and sequencing
Gene: GTF3C3 Amber List (moderate evidence)I don't know
Three unrelated individuals with variants in GTF3C3 all reported to have ID.
PMID: 30552426 reported on a patient with epilepsy and intellectual disability.
PMID: 28940097 reported on an individual who had a homozygous splice site variant which was shown to cause skipping of exon 10 and parts of exon 11 (in-frame deletion) in a patient with profound microcephaly, characteristic facial appearance and failure to thrive.
PMID: 28097321 reported on a homozygous missense variant in GTF3C3 in two affected sisters with a phenotype including mild ID, seizures and dysmorphisms and classified it as a moderately confident candidate gene.
GTF3C3 has no disease gene phenotype associations in OMIM or Gene2Phenotype and limited clinical information is provided on the degree of ID. All the cases identified have variable phenotype in terms of skeletal features and epilepsy. Therefore GTF3C3 will remain as Amber and be added to the watchlist.Created: 29 Jul 2019, 1:41 p.m. | Last Modified: 29 Jul 2019, 1:41 p.m.
Panel Version: 2.989
I don't know
Papuc et al. (PMID: 30552426) report on one further patient with epilepsy and intellectual disability (all participants of the study had moderate to profound ID) due to biallelic GTF3C3 mutations.
This individual had the following variants (NM_012086.4): c.2419C>T / p.(Arg807Cys) and c.503C>T / p.(Ala168Val). A healthy sister of the proband was heterozygous for the first variant but not the second one. The first variant affects only 1 (of 2) Refseq isoforms while the second affects both. Both variants were predicted pathogenic in silico and absent from ExAC.
The phenotype of previously published individuals (from PMIDs 28940097, 28097321) is briefly summarized. According to the authors, Tcf4 - a yeast ortholog of GTF3C3 - has been shown to interact with BRF1 for regulation of RNA polymerase III-mediated transcription. Arguments are provided for phenotypic similarities to the BRF1-related phenotype, cerebellofaciodental syndrome (MIM 616202).
The gene is not associated with any phenotype in OMIM, nor in G2P. It is not included in gene panels for ID offered by diagnostic laboratories.
As a result it could be considered for upgrade probably to amber (or green).Created: 19 Dec 2018, 11:41 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Global developmental delay; Intellectual disability; Seizures
Publications
I don't know
Two unrelated families with bi-allelic variants in this gene, ID is part of the phenotype. Consider inclusion as Amber.Created: 22 Jun 2018, 11:09 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Publications
Variants in this GENE are reported as part of current diagnostic practice
Gene: gtf3c3 has been classified as Amber List (Moderate Evidence).
Tag watchlist tag was added to gene: GTF3C3.
Phenotypes for gene: GTF3C3 were changed from to Global developmental delay; Intellectual disability; Seizures
Publications for gene: GTF3C3 were set to 28940097, 28097321
Source Victorian Clinical Genetics Services was added to GTF3C3.
GTF3C3 was added to Intellectual disability panel. Sources: Literature
GTF3C3 was created by Zornitza Stark
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 [email protected]
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.