Intellectual disability
Gene: EMC1

EMC1 (ER membrane protein complex subunit 1)
EnsemblGeneIds (GRCh38): ENSG00000127463
EnsemblGeneIds (GRCh37): ENSG00000127463
OMIM: 616846, Gene2Phenotype
EMC1 is in 4 panels

6 reviews

Arina Puzriakova (Genomics England Curator)

The mode of inheritance of this gene has been updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Created: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.

Panel Version: 4.53

Created: 30 Jan 2023, 5:50 p.m.
Last Modified: 30 Jan 2023, 5:50 p.m.
Panel version: 4.53

Eleanor Williams (Genomics England Curator)

Comment on mode of inheritance: 3 more cases of monoallelic variants in patients with an intellectual disability phenotype now reported so the mode of inheritance should be changed to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'
Created: 14 Aug 2022, 8:11 p.m. | Last Modified: 14 Aug 2022, 8:11 p.m.

Panel Version: 3.1677

As the expert reviewer notes, Chung et al 2022 (PMID: 35234901) report 3 unrelated children with severe to profound developmental delay, truncal hypotonia, seizures and cortical visual impairment. A c.1745C > A; p.Pro582His (de novo) variant in EMC1 was found in 2 of the individuals. The other child had EMC1 c.1745C > G; p.Pro582Arg (mosaic; not inherited from mother, father deceased). Variants were identified by WES and confirmed by Sanger sequencing. In a Drosophila model the identified variants didn't rescue the lethality of a null allele. They also found variations in dosage of the wild-type EMC1, specifically in glia, lead to pupal lethality.
Created: 14 Aug 2022, 8:10 p.m. | Last Modified: 14 Aug 2022, 8:10 p.m.

Panel Version: 3.1676

Created: 14 Aug 2022, 8:10 p.m.
Last Modified: 14 Aug 2022, 8:10 p.m.
Panel version: 3.1676

Dmitrijs Rots (Children's Clinical University Hospital)

Green List (high evidence)

With additional 3 cases + functional data - enough evindence now to include as monoallelic as well.
Created: 15 Jul 2022, 5:24 a.m. | Last Modified: 15 Jul 2022, 5:24 a.m.

Panel Version: 3.1627

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

PMID: 35234901

Created: 15 Jul 2022, 5:24 a.m.
Last Modified: 15 Jul 2022, 5:24 a.m.
Panel version: 3.1627

Helen Brittain (Genomics England Curator)

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

Created: 19 Jul 2019, 11:14 a.m.
Last Modified: 19 Jul 2019, 11:14 a.m.
Panel version: Imported from Intellectual disability update May 2019 panel version 0.202

Catherine Snow (Genomics England)

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

Created: 20 May 2019, 1:48 p.m.
Last Modified: 3 Jul 2019, 1:38 p.m.
Panel version: Imported from Intellectual disability update May 2019 panel version 0.33

Konstantinos Varvagiannis (Other)

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

Phenotypes
Cerebellar atrophy, visual impairment, and psychomotor retardation, MIM 616875

Publications

Variants in this GENE are reported as part of current diagnostic practice

Created: 20 Oct 2018, 1:52 a.m.

Panel version: 2.510

Details

Mode of Inheritance

BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Sources

NHS GMS
Expert Review Green
Literature

Phenotypes

Cerebellar atrophy, visual impairment, and psychomotor retardation, OMIM:616875

OMIM

616846

Clinvar variants

Variants in EMC1

Penetrance

Complete

Publications

Panels with this gene