EMC1

protein-coding

ER membrane protein complex subunit 1, the group of ER membrane protein complex subunits

Gene summary

This gene encodes a single-pass type I transmembrane protein, which is a subunit of the endoplasmic reticulum membrane protein complex (EMC). Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2012]

Previous symbols:

KIAA0090

MANE transcript

NM_015047.3

Inheritance

AR, AD

ClinVar variants

P:114U:710B:314

Top phenotype

Cerebellar atrophy, visual impairment, and psychomotor retardation

gnomAD constraint

pLI —, LoF o/e 0.79

Max pathogenic AF

—

Genomic locus

chr1:19,215,660-19,251,552

External References & Databases

Ensembl (ENSG00000127463)

Transcript & Mutation Effects

hg38 • Region Span ~35.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cerebellar atrophy, visual impairment, and psychomotor retardation;STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014811

Submitter: G2P

cerebellar atrophy, visual impairment, and psychomotor retardation;LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014811

Submitter: G2P

cerebellar atrophy, visual impairment, and psychomotor retardation;STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014811

Submitter: Labcorp Genetics (formerly Invitae)

global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018822

Submitter: Orphanet

cerebellar atrophy, visual impairment, and psychomotor retardation;MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014811

Submitter: Ambry Genetics

complex neurodevelopmental disorder with motor featuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100516

Submitter: PanelApp Australia

complex neurodevelopmental disorder with motor featuresSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100516

Submitter: PanelApp Australia

complex neurodevelopmental disorder with motor featuresMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100516

Submitter: ClinGen

EMC1 is a component of the EMC complex, a multifunctional, multi-subunit protein complex involved in insertion of trans-membrane domains with low hydrophobicity into the ER membrane. *EMC1* was first reported in relation to autosomal dominant complex neurodevelopmental disorder with motor features in 2016 (Harel et al., PMID 26942288). *EMC1* has been noted to be associated with the following disease entities: Cerebellar atrophy, visual impairment, and psychomotor retardation (MIM:616875) and Global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome (ORPHA:480898). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in inheritance pattern. The split curation for autosomal recessive complex neurodevelopmental disorder with motor features has been curated separately. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 4 POINTS. 4 unique variants (all missense variants) that have been reported in 4 probands in 2 publications (PMIDs: 26942288, 35234901) are included in this curation. Structural modelling suggests that these variants cluster within the beta-propeller domain of the EMC1 protein (PMID: 35234901). For 3/4 of these variants, additional functional evidence is provided by failure of the mutant proteins to rescue phenotypes in a Drosophila model. This gene-disease association is also further supported by this Drosophila model, where knockdown in glia resulted in reduced viability and a motor phenotype which were rescued by expression of human wildtype *EMC1* (PMID: 35234901). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Cerebral Palsy GCEP on the meeting date 6th October 2022 (SOP Version 9).

complex neurodevelopmental disorder with motor featuresMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0100516

Submitter: ClinGen

EMC1 is a component of the EMC complex, a multifunctional, multi-subunit protein complex involved in insertion of trans-membrane domains with low hydrophobicity into the ER membrane. *EMC1* was first reported in relation to autosomal recessive complex neurodevelopmental disorder with motor features in 2016 (Harel et al., PMID 26942288). *EMC1* has been noted to be associated with the following disease entities: Cerebellar atrophy, visual impairment, and psychomotor retardation (MIM:616875) and Global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome (ORPHA:480898). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in inheritance pattern in some reported cases. The split curation for autosomal dominant complex neurodevelopmental disorder with motor features has been curated separately. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 8 POINTS. 6 unique variants (including 3 missense, 1 nonsense, 1 frameshift, and 1 splicing) that have been reported in 5 probands in 3 publications (PMIDs: 26942288, 29271071, 32092440) are included in this curation. This gene-disease association is also supported by a Drosophila model, where knockdown in glia resulted in reduced viability and a motor phenotype which were rescued by expression of human *EMC1* (PMID: 35234901). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Cerebral Palsy GCEP on the meeting date 3rd November 2022 (SOP Version 9).

Clinical Genomic Database (CGD)

Cerebellar atrophy, visual impairment, and psychomotor retardationAR

Manifestation: Craniofacial; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 26942288

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EMC1 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 1333

Inborn genetic diseasesTotal: 157

not specifiedTotal: 110

Cerebellar atrophy, visual impairment, and psychomotor retardation;Total: 64

Retinal dystrophyTotal: 52

EMC1-related disorderTotal: 41

Global developmental delayTotal: 2

Cerebellar atrophyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015047.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	17 clinvar	283 clinvar	3 clinvar	304
missense	1 clinvar	9 clinvar	671 clinvar	26 clinvar	2 clinvar	709
nonsense	15 clinvar	14 clinvar	4 clinvar			33
start loss	1 clinvar	2 clinvar				3
frameshift	24 clinvar	14 clinvar	7 clinvar			45
splice donor/acceptor (+/-2bp)		33 clinvar	11 clinvar			44
Total	41	73	710	309	5	1138

Highest pathogenic variant AF is 0.00014002305

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 88 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015047.3	RefSeq	NP_055862.1	23	MANE Select
ENST00000477853.6	Ensembl	ENSP00000420608.1	23	MANE Select
NM_001271427.2	RefSeq	NP_001258356.1	23	Standard
NM_001271428.2	RefSeq	NP_001258357.1	23	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein folding in endoplasmic reticulum

Cellular Component

integral component of membrane
protein-containing complex
ER membrane protein complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000477853
Coding exons: 23
Length: 35889
Individuals with no LoFs: 125582
Homozygous LoFs: 0
Heterozygous LoFs: 166
Defined: 125748
p: 0.000660

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.35	493	585	0.843	0.0000345	6421
Missense (PolyPhen)		150	197.13	0.76093		2068
Synonymous	1.54	205	235	0.872	0.0000137	2037
Loss of Function	1.49	46	58.3	0.789	0.00000314	599

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00055	0.00055	rare
Latino/Admixed American	0.00087	0.00087	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00065	0.00065	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00067	0.00067	rare
South Asian	0.00098	0.00098	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Cerebellar atrophy, visual impairment, and psychomotor retardation (CAVIPMR) [MIM:616875]: An autosomal recessive, neurodegenerative disorder characterized by developmental delay, intellectual disability, hypotonia, scoliosis, cerebellar atrophy, and variable dysmorphic features. {ECO:0000269|PubMed:26942288}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.113

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): K

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium