VCV000012774.6 - ClinVar

NM_002354.3(EPCAM):c.499dup (p.Gln167fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002354.3(EPCAM):c.499dup (p.Gln167fs)

Variation ID: 12774 Accession: VCV000012774.6

Type and length

Duplication, 1 bp

Location

Cytogenetic: 2p21 2: 47377020-47377021 (GRCh38) [ NCBI UCSC ] 2: 47604159-47604160 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 22, 2016	Oct 8, 2024	May 8, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_002354.3:c.499dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002345.2:p.Gln167fs	frameshift
NM_002354.3:c.499dupC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_002354.2:c.499dupC
NC_000002.12:g.47377021dup
NC_000002.11:g.47604160dup
NG_012352.2:g.36859dup
LRG_215:g.36859dup

... more HGVS ... less HGVS

Protein change

Q167fs

Other names

Canonical SPDI

NC_000002.12:47377020:C:CC

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA122702 OMIM: 185535.0004 dbSNP: rs606231204 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
EPCAM		-	-	GRCh38 GRCh37	772	876

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Congenital diarrhea 5 with tufting enteropathy	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	May 8, 2023	RCV000013612.29
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 7, 2021	RCV000521713.3
EPCAM-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 9, 2024	RCV004751210.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (May 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Congenital diarrhea 5 with tufting enteropathy Affected status: yes Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV003924284.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023
Pathogenic (Feb 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital diarrhea 5 with tufting enteropathy Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848899.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The p.Gln167ProfsX21 variant in EPCAM has been reported in >20 homozygous individuals and 2 compound heterozygous individuals with congenital diahrrea with tufting enteropathy and and … (more) The p.Gln167ProfsX21 variant in EPCAM has been reported in >20 homozygous individuals and 2 compound heterozygous individuals with congenital diahrrea with tufting enteropathy and and segregated with disease in at least 1 affected individuals from 1 family. It is thought to be a founder mutation in the Gulf communities (Al-Mayouf 2009 PMID: 19820410, Salomon 2011 PMID: 21315192, Salomon 2014 PMID: 24142340, AlMahamed 2017 PMID: 28361844). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 12774). Immunohistochemistry on cases and controls showed no staining for EPCAM on the intercellular memebrane in individuals homozygous for the variant (Salomon 2011 PMID: 21315192, Schnell 2013 PMID: 23462293, Alfares 2017 PMID: 28454995). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 167 and leads to a premature termination codon 21 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the EPCAM gene is an established disease mechanism in autosomal recessive congenital diahrrea with tufting enteropathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital diahrrea with tufting enteropathy. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting, PP1, PS3_Supporting. (less)
Pathogenic (Dec 07, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000617398.3 First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect (Schnell et al., 2013); Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to … (more) Published functional studies demonstrate a damaging effect (Schnell et al., 2013); Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19820410, 21315192, 23462293, 28361844, 24142340, 28454995, 30202406, 30461124, 31462756, 32483295, 32735948) (less)
Pathogenic (Mar 01, 2014)	no assertion criteria provided Method: literature only	DIARRHEA 5, WITH TUFTING ENTEROPATHY, CONGENITAL Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033859.3 First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016	Publications: PubMed (4) PubMed: 19820410‚ 21315192‚ 23462293‚ 24142340 Comment on evidence: In a patient born of first-cousin parents, who had congenital tufting enteropathy (DIAR5; 613217) and developed chronic inflammatory arthritis at 4 years of age, Al-Mayouf … (more) In a patient born of first-cousin parents, who had congenital tufting enteropathy (DIAR5; 613217) and developed chronic inflammatory arthritis at 4 years of age, Al-Mayouf et al. (2009) identified homozygosity for a 1-bp insertion (c.498insC) in exon 5 of the EPCAM gene, causing a frameshift resulting in a premature termination codon (Gln167ProfsTer21). In affected individuals from 4 unrelated consanguineous Kuwaiti families and 1 consanguineous Qatari family, who had severe neonatal diarrhea and typical tufting on intestinal biopsies, Salomon et al. (2011) identified homozygosity for the c.498insC mutation in the EPCAM gene. The mutation was not found in 119 ethnically matched controls. In 2 additional patients from unrelated Kuwaiti families, the c.498insC mutation was found in compound heterozygosity with a splice site mutation (185535.0008). Both mutations were predicted to truncate the C-terminal domain necessary for anchorage of EPCAM at the intercellular membrane, and immunohistochemistry of intestinal biopsies failed to detect EPCAM protein at this membrane. Haplotype analysis using microsatellite markers revealed that carriers of the c.498insC mutation shared a minimal common haplotype of 473 kb, consistent with a founder effect that occurred approximately 5,000 to 6,000 years earlier (190 generations removed) in this population. In immunostained transfected HEK293T cells, Schnell et al. (2013) observed that the 498insC mutant was minimally detectable and was not present at the cell surface, in contrast to wildtype EPCAM. Western blot analysis indicated that the truncated mutant is expressed, leading the authors to suggest that it is likely degraded. Salomon et al. (2014) noted that the c.498insC mutation is sometimes designated c.499dup. (less)
Pathogenic (May 02, 2018)	no assertion criteria provided Method: clinical testing	Congenital diarrhea 5 with tufting enteropathy Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV000854667.1 First in ClinVar: Aug 22, 2016 Last updated: Aug 22, 2016
Pathogenic (Jul 09, 2024)	no assertion criteria provided Method: clinical testing	EPCAM-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005345957.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The EPCAM c.499dupC variant is predicted to result in a frameshift and premature protein termination (p.Gln167Profs21). This variant has been reported in the homozygous state … (more) The EPCAM c.499dupC variant is predicted to result in a frameshift and premature protein termination (p.Gln167Profs21). This variant has been reported in the homozygous state in multiple consanguineous families with individuals presenting with congenital tufting enteropathy (Al-Mayouf et al. 2009. PubMed ID: 19820410; AlMahamed et al. 2017, PubMed ID: 28361844; Saloman et al. 2011. PubMed ID: 21315192, reported as c.498insC). Functional studies in vitro demonstrate that this variant leads to absent cell-surface EPCAM protein expression (Schnell et al. 2013, Figure 2. PubMed ID: 23462293). In addition, duodenal biopsy sections from patients homozygous for this variant are absent of intercellular staining of EPCAM (Saloman et al. 2011. PubMed ID: 21315192). This variant has not been reported in a large population database, and is reported in ClinVar as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/12774/). Frameshift variants in EPCAM are expected to be pathogenic. This variant is interpreted as pathogenic. (less)

Comment:

The p.Gln167ProfsX21 variant in EPCAM has been reported in >20 homozygous individuals and 2 compound heterozygous individuals with congenital diahrrea with tufting enteropathy and and segregated with disease in at least 1 affected individuals from 1 family. It is thought to be a founder mutation in the Gulf communities (Al-Mayouf 2009 PMID: 19820410, Salomon 2011 PMID: 21315192, Salomon 2014 PMID: 24142340, AlMahamed 2017 PMID: 28361844). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 12774). Immunohistochemistry on cases and controls showed no staining for EPCAM on the intercellular memebrane in individuals homozygous for the variant (Salomon 2011 PMID: 21315192, Schnell 2013 PMID: 23462293, Alfares 2017 PMID: 28454995). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 167 and leads to a premature termination codon 21 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the EPCAM gene is an established disease mechanism in autosomal recessive congenital diahrrea with tufting enteropathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital diahrrea with tufting enteropathy. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting, PP1, PS3_Supporting.

Comment:

Published functional studies demonstrate a damaging effect (Schnell et al., 2013); Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19820410, 21315192, 23462293, 28361844, 24142340, 28454995, 30202406, 30461124, 31462756, 32483295, 32735948)

Comment:

The EPCAM c.499dupC variant is predicted to result in a frameshift and premature protein termination (p.Gln167Profs*21). This variant has been reported in the homozygous state in multiple consanguineous families with individuals presenting with congenital tufting enteropathy (Al-Mayouf et al. 2009. PubMed ID: 19820410; AlMahamed et al. 2017, PubMed ID: 28361844; Saloman et al. 2011. PubMed ID: 21315192, reported as c.498insC). Functional studies in vitro demonstrate that this variant leads to absent cell-surface EPCAM protein expression (Schnell et al. 2013, Figure 2. PubMed ID: 23462293). In addition, duodenal biopsy sections from patients homozygous for this variant are absent of intercellular staining of EPCAM (Saloman et al. 2011. PubMed ID: 21315192). This variant has not been reported in a large population database, and is reported in ClinVar as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/12774/). Frameshift variants in EPCAM are expected to be pathogenic. This variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic characterization of congenital tufting enteropathy: epcam associated phenotype and involvement of SPINT2 in the syndromic form.	Salomon J	Human genetics	2014	PMID: 24142340
Absence of cell-surface EpCAM in congenital tufting enteropathy.	Schnell U	Human molecular genetics	2013	PMID: 23462293
A founder effect at the EPCAM locus in Congenital Tufting Enteropathy in the Arabic Gulf.	Salomon J	European journal of medical genetics	2011	PMID: 21315192
Tufting enteropathy and chronic arthritis: a newly recognized association with a novel EpCAM gene mutation.	Al-Mayouf SM	Journal of pediatric gastroenterology and nutrition	2009	PMID: 19820410

Text-mined citations for rs606231204 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_002354.3(EPCAM):c.499dup (p.Gln167fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs606231204 ...