Intellectual disabilityGene: EMC1 Green List (high evidence)
Green List (high evidence)
In view of the three unrelated cases with biallelic variants, I consider this to be sufficient evidence for inclusion as green. I would only recommend this is in the context of biallelic variants however. There is only one case reported with a de novo heterozygous variant, therefore I feel further information in terms of more cases or understanding the spectrum of variants / functional effect of these is needed prior to prioritising monoallelic variants in addition. I have therefore changed the MOI to biallelic only.
Created: 19 Jul 2019, 11:14 a.m. | Last Modified: 19 Jul 2019, 11:14 a.m.
Panel Version: 0.202
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Comment on list classification: EMC1 identified in literature PMID:30914295 as missing in PanelApp compared to other curated gene list for ID genes.
EMC1 has also been reviewed Green by Konstantinos Varvagiannis and is in OMIM and G2P as "Disease: Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy.".
Harel et al. (PMID: 26942288) describes 4 individual families. Family 1-3 has three different biallelic homozygous variants. Family 4 has monoallelic, de novo hetrozygous variants. However additional evidence of EMC1 comes from Geetha et al. (PMID: 29271071) who reported on an additional individual with biallelic homozygous intronic variant, affected the splice sight and resulted in the retention of intron 11.
It has been noted that the phenotype severity is broad from severe to moderate developmental delay and because of this the authors propose that both monoallelic and biallelic pathogenic variants may be causative of the specific phenotype, though the presentation may be more severe in case of biallelic variants.
As there are sufficient number of families and variants EMC1 can be classified as Green.
Created: 20 May 2019, 1:48 p.m. | Last Modified: 3 Jul 2019, 1:38 p.m.
Panel Version: 0.196
Green List (high evidence)
Harel et al. (PMID: 26942288) describe 7 individuals from 3 families with biallelic pathogenic variants in EMC1.
In the first family, a single individual (born to non-consanguineous parents) was found to harbor a homozygous frameshift variant in a small (approx. 100 kb) stretch of absence of heterozygosity. The patients in the other two families were homozygous for missense variants (private to each family) in the context of parental consanguinity.
The common phenotype was suggestive of a progressive neurodegenerative disorder and consisted of hypotonia, severe developmental delay with marked speech delay, diminished deep tendon reflexes, cerebellar atrophy, vision as well as skeletal problems. Seizures were a feature in one subject.
One further patient from an additional (fourth) family was found to have a similar but milder phenotype and was only found to harbor a de novo missense variant in EMC1 following trio exome sequencing. Sanger sequencing of the promoter region as well as CNV calling from the exome data failed to reveal other variants in this specific individual.
Similarly to what has been observed in other genes the authors propose that both monoallelic and biallelic pathogenic variants may be causative of the specific phenotype, though the presentation may be more severe in case of biallelic variants.
Altogether this study reports 1 homozygous frameshift and 3 missense variants (2 of the latter found in homozygous state and one as a de novo heterozygous mutation). //
Geetha et al. (PMID: 29271071) describe an individual born to consanguineous parents presenting with hypotonia, developmental delay, and cerebellar atrophy as well as early onset epilepsy. Exome sequencing demonstrated a homozygous splice variant in EMC1. This variant was demonstrated to result to retention of intron 11 upon RNA sequencing. This was predicted to lead to premature truncation of the protein. //
EMC1 is associated in OMIM with Cerebellar atrophy, visual impairment, and psychomotor retardation (MIM 616875) for which an autosomal recessive inheritance mode is retained. //
Apart from the variants reported in the previous studies [p.Pro874Argfs*21, p.Thr82Met, p.Gly868Arg, p.Gly471Arg, c.1212+1G>A - NM_015047.2] further variants have been submitted in ClinVar as likely pathogenic (Variation IDs : 521479, 445564). //
The gene has been included in intellectual disability gene panels offered by a few other diagnostic labs. //
As a result this gene can be considered for inclusion in the panel as green (or amber).
Sources: Expert Review, Literature
Created: 20 Oct 2018, 1:52 a.m.
Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Cerebellar atrophy, visual impairment, and psychomotor retardation, MIM 616875
Variants in this GENE are reported as part of current diagnostic practice
Mode of inheritance for gene EMC1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Source Expert Review Green was added to EMC1. Added phenotypes Cerebellar atrophy, visual impairment, and psychomotor retardation, 616875 for gene: EMC1 Publications for gene EMC1 were changed from 26942288; 29271071 to 29271071; 26942288; 30914295 Rating Changed from No List (delete) to Green List (high evidence)
gene: EMC1 was added gene: EMC1 was added to Intellectual disability. Sources: Expert Review,Literature Mode of inheritance for gene: EMC1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: EMC1 were set to 26942288; 29271071 Phenotypes for gene: EMC1 were set to Cerebellar atrophy, visual impairment, and psychomotor retardation, MIM 616875 Penetrance for gene: EMC1 were set to Complete Review for gene: EMC1 was set to GREEN gene: EMC1 was marked as current diagnostic
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).
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).
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.
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
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.