Intellectual disability - microarray and sequencing
Gene: TRMT1 Green List (high evidence)As a result of watchlist tag audit the watchlist tag was removed from TRMT1- this is now a green gene with sufficient evidence/review. Noted as being removed but this was not updated in the database.Created: 13 Jan 2020, 4:19 p.m. | Last Modified: 13 Jan 2020, 4:19 p.m.
Panel Version: 3.0
Green List (high evidence)
PMID: 30289604 reports on 4 additional patients from 2 unrelated consanguineous Pakistani families.
One subject was homozygous for a previously described frameshift variant. Affected individuals from the second family were homozygous for a novel splice-site variant.
The phenotype of the new patients as well as of previously published ones (PMID: 21937992, 26308914) is summarized.
In total 9 individuals from 4 families have been reported. ID was a universal feature (9/9). Seizures have been reported in 4 individuals from 2 families. Primary microcephaly was observed in the 4 new patients but was not the case for the rest of the cohort.
3 loss-of-function variants have been observed in total.
PMID: 28784718 provides extensive functional evidence for the 2 variants reported in 3 of the families.
TRMT1 is included in gene panels for intellectual disability offered by different diagnostic laboratories.
As a result, this gene can be considered for upgrade to green.Created: 5 Dec 2018, 2:34 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Global developmental delay; Intellectual disability; Seizures; Microcephaly
Publications
Variants in this GENE are reported as part of current diagnostic practice
Red List (low evidence)
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
AUTOSOMAL RECESSIVE MENTAL RETARDATION
Publications
I don't know
Removed 'watchlist' tag following promotion of gene rating from Amber to Green.Created: 14 May 2019, 1:35 p.m.
Comment on list classification: Updated rating from Amber to Green based on the additional recent publication provided by Konstantinos Varvagiannis. PMID:30289604 (Blaesius et al., 2018) report 4 further patients from 2 unrelated consanguineous Pakistani families with homozygous variants in TRMT1 (a 32 bp deletion, and a G>T transversion predicted to result in aberrant splicing and LOF). All four patients had mild-to -moderate intellectual disability. This brings the total number of unrelated cases to four (the previous two cases coming from PMIDs:21937992 and PMID:26308914) . With functional studies in PMID:28784718 (Dewe et al., 2017), there is now sufficient evidence for a Green (diagnostic-grade) rating.Created: 14 May 2019, 1:30 p.m.
2 Iranian families reported so far with TRMT1 variants and autosomal recessive ID from PMID:21937992 (2011) and PMID:26308914 (2015). Possible DD-G2P gene for AUTOSOMAL RECESSIVE MENTAL RETARDATION. Rated as Amber because further cases required to rate as diagnostic-grade.Created: 29 Nov 2017, 11:19 a.m.
Added 'watchlist' tag to collect further publications (in addition to PMID:21937992 and PMID:26308914) to support ID causation.Created: 5 Oct 2017, 2:43 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
autosomal recessive intellectual disorder; ARID
Publications
Red List (low evidence)
Tag watchlist was removed from gene: TRMT1.
Phenotypes for gene: TRMT1 were changed from autosomal recessive intellectual disorder; ARID to autosomal recessive intellectual disorder; ARID; Mental retardation, autosomal recessive 68, 618302; Global developmental delay; Intellectual disability
Publications for gene: TRMT1 were set to 21937992; 26308914
Gene: trmt1 has been classified as Green List (High Evidence).
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
Expert Review Amber was added to TRMT1. Panel: Intellectual disability Publications for gene TRMT1 was set to ['21937992', ' 26308914']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
TRMT1 was added to Intellectual disabilitypanel. Sources: Expert Review Red
TRMT1 was created by ellenmcdonagh
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.