Mendeliome
Gene: TOR1AIP1 Green List (high evidence)Green List (high evidence)
Gene is associated with multiple muscle phenotypes as already noted. Single family myasthenic syndrome and supportive mouse model data.Created: 19 Aug 2021, 4:21 a.m. | Last Modified: 19 Aug 2021, 4:21 a.m.
Panel Version: 0.8881
Comment when marking as ready: Highly variable phenotype. Few of the features are consistently reported across affected individuals.Created: 1 Jun 2020, 6:25 a.m. | Last Modified: 1 Jun 2020, 6:25 a.m.
Panel Version: 0.2971
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Congenital myasthenic syndrome
Publications
Green List (high evidence)
2 further unrelated individuals reported with:
congenital bilateral hearing loss, ventricular septal defect, bilateral cataracts, mild to moderate developmental delay, microcephaly, mandibular hypoplasia, short stature, progressive muscular atrophy, joint contractures and severe chronic heart failure, with much longer survival.
- Condition considered to be a 'nuclear envelopathy'
- Patients survivied beyond the 1st decade of life
- Compound heterozygous PTCs and missense reported (affecting both LAP1 isoforms)
- Functional studies showed a loss of function
History: "biallelic pathogenic variants in TOR1AIP1... have been described in a family with three individuals affected by muscular dystrophy with variable cardiac involvement (Kayman-Kurekci et al. 2014), in a boy affected by dystonia, cerebellar atrophy, and cardiomyopathy (Dorboz et al. 2014), and in two siblings affected by cardiac failure and muscular dystrophy (Ghaoui et al. 2016). Furthermore, a recent study identified a homozygous Palestinian founder variant, p.(Arg321*), in seven individuals from five likely related families affected by early onset multisystem anomalies with progeroid appearance and lethality in the 1st decade of life (Fichtman et al. 2019). Only those bearing the p.(Arg321*) had a loss of both LAP1B and LAP1C protein isoforms."Created: 1 Jun 2020, 6:03 a.m. | Last Modified: 1 Jun 2020, 6:03 a.m.
Panel Version: 0.2966
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
TOR1AIP1-associated nuclear envelopathy
Publications
Green List (high evidence)
Comment on list classification: Phenotype appears to be variable depending on which isoform is affected by the variants.Created: 12 Feb 2020, 1:58 a.m. | Last Modified: 12 Feb 2020, 1:58 a.m.
Panel Version: 0.1339
At least 5 families/cases reported with muscular dystrophy and sometimes cardiomyopathy.
Sources: Expert listCreated: 12 Feb 2020, 1:53 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072
Publications
Phenotypes for gene: TOR1AIP1 were changed from Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072; Progeroid appearance; Cataracts; Microcephaly; Deafness; Contractures to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072; Congenital myasthenic syndrome
Publications for gene: TOR1AIP1 were set to 24856141; 31299614; 30723199; 27342937; 32055997
Phenotypes for gene: TOR1AIP1 were changed from Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072; Progeroid appearance; Cataracts; Microcephaly; Deafness to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072; Progeroid appearance; Cataracts; Microcephaly; Deafness; Contractures
Phenotypes for gene: TOR1AIP1 were changed from Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072 to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072; Progeroid appearance; Cataracts; Microcephaly; Deafness
Gene: tor1aip1 has been classified as Green List (High Evidence).
Publications for gene: TOR1AIP1 were set to 24856141; 31299614; 30723199; 27342937
Gene: tor1aip1 has been classified as Green List (High Evidence).
Gene: tor1aip1 has been classified as Green List (High Evidence).
gene: TOR1AIP1 was added gene: TOR1AIP1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: TOR1AIP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TOR1AIP1 were set to 24856141; 31299614; 30723199; 27342937 Phenotypes for gene: TOR1AIP1 were set to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures MIM#617072 Review for gene: TOR1AIP1 was set to GREEN
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.