NM_020964.3(EPG5):c.6232C>T (p.Arg2078Ter) AND Vici syndrome

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Dec 9, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000033118.16

Allele description [Variation Report for NM_020964.3(EPG5):c.6232C>T (p.Arg2078Ter)]

NM_020964.3(EPG5):c.6232C>T (p.Arg2078Ter)

Gene:

EPG5:ectopic P-granules 5 autophagy tethering factor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q12.3

Genomic location:

Preferred name:

NM_020964.3(EPG5):c.6232C>T (p.Arg2078Ter)

HGVS:

NC_000018.10:g.45867742G>A
NG_042838.1:g.104598C>T
NM_020964.3:c.6232C>TMANE SELECT
NP_066015.2:p.Arg2078Ter
LRG_1234t1:c.6232C>T
LRG_1234:g.104598C>T
LRG_1234p1:p.Arg2078Ter
NC_000018.9:g.43447707G>A
NM_020964.2:c.6232C>T

Protein change:

R2078*; ARG2078TER

Links:

OMIM: 615068.0005; dbSNP: rs587776942

Molecular consequence:

NM_020964.3:c.6232C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Vici syndrome (VICIS)
Identifiers:: MONDO: MONDO:0009452; MedGen: C1855772; Orphanet: 1493; OMIM: 242840

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000056899	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 2013)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000247310	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000899147	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 17, 2019)	unknown	curation	PubMed (2) [See all records that cite these PMIDs] 23222957, 25741868
SCV004297835	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 5, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23674064, 23222957, 28492532
SCV006585363	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 9, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23222957, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Role of Epg5 in selective neurodegeneration and Vici syndrome.

Zhao YG, Zhao H, Sun H, Zhang H.

Autophagy. 2013 Aug;9(8):1258-62. doi: 10.4161/auto.24856. Epub 2013 May 14.

PubMed [citation]

PMID:: 23674064
PMCID:: PMC3748201

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000056899.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

For discussion of the arg2078-to-ter (R2078X) mutation in the EPG5 gene that was found in compound heterozygous state in 2 sibs with Vici syndrome (VICIS; 242840) by Cullup et al. (2013), see 615068.0004.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV000247310.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From SIB Swiss Institute of Bioinformatics, SCV000899147.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

This variant is interpreted as a Pathogenic for Vici syndrome, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PVS1 => Predicted nullvariant in a gene where LOF is a known mechanism of disease. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:23222957).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004297835.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Arg2078*) in the EPG5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EPG5 are known to be pathogenic (PMID: 23222957, 23674064). This variant is present in population databases (rs587776942, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Vici syndrome (PMID: 23222957). ClinVar contains an entry for this variant (Variation ID: 39984). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV006585363.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000039984 /PMID: 23222957). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 23, 2026

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