EPG5

protein-coding

ectopic P-granules 5 autophagy tethering factor

Gene summary

This gene encodes a large coiled coil domain-containing protein that functions in autophagy during starvation conditions. Mutations in this gene cause Vici syndrome. [provided by RefSeq, Aug 2015]

Previous symbols:

KIAA1632

MANE transcript

NM_020964.3

Inheritance

ClinVar variants

P:231U:970B:866

Top phenotype

Vici syndrome

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr18:45,800,581-45,967,329

External References & Databases

Ensembl (ENSG00000152223)

Transcript & Mutation Effects

hg38 • Region Span ~166.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Vici syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009452

Submitter: Ambry Genetics

Vici syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009452

Submitter: Ambry Genetics

Vici syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009452

Submitter: ClinGen

Vici syndrome was first reported in PMID:3344762 by Vici et al. This condition is characterized by central features of agenesis or thinning of corpus callosum, developmental delay/intellectual disability, comined immunodeficiency with signs of thymic aplasia/hypoplasia, cardiomyopathy, cataracts, and microcephaly. To date approximately 90 individuals have been reported with biallelic variants in *EPG5* (Dafsari, Gene reviews 2022). In this curation, 12 variants were scored including frameshift, missense, nonsense, and splice site variants across 7 probands from 4 publications (PMIDs:26395118, 23222957, 26917586, 344762) to reach a maximum score of genetic evidence. Heterozygous parents and siblings were unaffected. The mechanism of pathogenicity is loss of function. This gene-disease association is also supported by the biochemical function of EPG5 (PMID:27588602).EPG5 is a protein involved in autophagy, which facilitates fusion specificity of autophagosomes with late endosomes and lysosomes. Patient fibroblasts have been shown to have impaired autophagy. Multi-system effects may be due to disrupted autophagy function, which plays a crucial role in cell homeostasis through the recycling/ degredation of protein products/organelles and the role of autophagy pathways in immune system defense. Additionally, the gene-disease relationship is supported by knock out *EPG5* (-/-) mice (PMID: 23674064). *EPG5* knockout mice recapitulated the phenotypes of pathologic corpus callosum changes and myopathy, including an increase in centrally located nuclei. However, knock out *EPG5* mice grew to be sexually active adults and failed to recapitulate phenotypes such as facial dysmorphia, hypopigmentation, immunodeficiency phenotypes cataracts, and cardiac changes. Finally, the gene-disease relationship is supported by knock out *EPG5* zebrafish (PMID: 30806141). *EPG5* (-/-) zebrafish displayed phenotypes such as cardiomyopathy, growth impairment, and perhaps most notably, defective autophagy pathway and features of myopathy. In summary, there is definitive evidence to support this gene-disease relationship.

Vici syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009452

Submitter: G2P

Vici syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009452

Submitter: PanelApp Australia

Vici syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009452

Submitter: Orphanet

Vici syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009452

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Vici syndromeAR

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Cardiovascular

Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Surveillance for cardiomyopathy (eg, including echocardiogram) may allow early management; Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 20186778; 23222957; 27343256; 28168853

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EPG5 variants in ClinVar

13 Conditions Cataloged

Vici syndromeTotal: 2251

Inborn genetic diseasesTotal: 370

not providedTotal: 283

not specifiedTotal: 249

EPG5-related disorderTotal: 111

EPG5-related disordersTotal: 15

Neurodevelopmental disorder with parkinsonism or other movement abnormalitiesTotal: 6

MicrocephalyTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020964.3. 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	5 clinvar	784 clinvar	4 clinvar	794
missense	2 clinvar	8 clinvar	943 clinvar	69 clinvar	9 clinvar	1031
nonsense	64 clinvar	29 clinvar	7 clinvar			100
start loss		1 clinvar	1 clinvar			2
frameshift	67 clinvar	23 clinvar	6 clinvar			96
splice donor/acceptor (+/-2bp)	8 clinvar	28 clinvar	8 clinvar			44
Total	141	90	970	853	13	2067

Highest pathogenic variant AF is 0.000028214687

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020964.3	RefSeq	NP_066015.2	44	MANE Select
ENST00000282041.11	Ensembl	ENSP00000282041.4	44	MANE Select
NM_001410858.1	RefSeq	NP_001397787.1	44	Standard
NM_001410859.1	RefSeq	NP_001397788.1	44	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

autophagy
autophagosome maturation

Cellular Component

cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000282041
Coding exons: 44
Length: 119667
Individuals with no LoFs: 124715
Homozygous LoFs: 0
Heterozygous LoFs: 112
Defined: 124827
p: 0.000449

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.08	1233	1.34e+3	0.917	0.0000699	16923
Missense (PolyPhen)		598	690.76	0.86571		9074
Synonymous	-0.950	548	520	1.05	0.0000282	4979
Loss of Function	6.88	48	134	0.358	0.00000684	1556

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00052	0.00045	rare
Latino/Admixed American	0.00079	0.00078	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00056	0.00056	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00045	0.00045	rare
South Asian	0.00033	0.00033	rare
Other	0.00050	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in autophagy. May play a role in a late step of autophagy, such as clearance of autophagosomal cargo. {ECO:0000269|PubMed:20550938, ECO:0000269|PubMed:23222957}.;
Disease: DISEASE: Vici syndrome (VICIS) [MIM:242840]: A rare congenital multisystem disorder characterized by agenesis of the corpus callosum, cataracts, pigmentary defects, progressive cardiomyopathy, and variable immunodeficiency. Affected individuals also have profound psychomotor retardation and hypotonia due to a myopathy. {ECO:0000269|PubMed:23222957}. Note=The disease is caused by mutations affecting the gene represented in this entry. Affected individuals show homozygosity or compound heterozygosity for truncating mutations, aberrant splicing and/or missense mutations. Parental studies suggest recessive inheritance with no carrier manifestation (PubMed:23222957). {ECO:0000269|PubMed:23222957}.;

Recessive Scores

pRec: 0.0999

Intolerance Scores

RVIS EVS: -0.36
RVIS percentile EVS: 28.31

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High