ClinVar Genomic variation as it relates to human health

This variant was identified as homozygous

For these reasons, this variant has been classified as Pathogenic. In cDNA sequence analysis using patient-derived RNA, this variant resulted in a frameshift caused by abnormal splicing (PMID: 24142340). An experimental study using cells expressing the truncated protein (p.Tyr186Phefs*6) has shown that this truncated protein lacks the transmembrane domain of EPCAM, resulting in loss of cell-surface EPCAM protein, and reduced protein secretion in vitro (PMID: 23462293). This variant has been reported in multiple individuals affected with congenital tufting enteropathy (CTE) (PMID: 23462293, 24142340, 28701297). ClinVar contains an entry for this variant (Variation ID: 157603). This variant is present in population databases (rs376155665, ExAC 0.01%). This sequence change falls in intron 5 of the EPCAM mRNA. It has been shown to affect mRNA splicing through the creation of new splice acceptor site, which causes a frameshift at codon 186 and creates a premature translational stop signal (p.Tyr186Phefs*6) (PMID: 23462293, 24142340). It is expected to result in an absent or disrupted protein product.

The c.556-14A>G variant in EPCAM has been reported in 10 individuals with congenital tufting enteropathy, at least 3 of which were homozygous or had additional variants in EPCAM (Schnell 2013 PMID: 23462293, Salomon 2014 PMID: 24142340, Bodian 2017 PMID: 28701297). One of these individuals had absence of EPCAM cell surface expression (Bodian 2017 PMID: 28701297). It segregated with disease in 2 affected family members from 2 families (Salomon 2014 PMID: 24142340, Bodian 2017 PMID: 28701297). It has also been identified in 0.02% (1/5192) of East Asian and 0.01% (1/15268) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 157603). Studies have shown that this intronic variant creates a new acceptor site within intron 5, which is predicted to create a framshift variant p.Tyr186PhefsX6. Studies have also shown that this variant causes loss of cell-surface EpCAM (Schnell 2013 PMID: 23462293, Salomon 2014 PMID: 24142340). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive congenital tufting enteropathy. ACMG/AMP Criteria applied: PM3, PS3, PP1_Moderate.

The EPCAM c.556-14A>G intronic change results in an A to G substitution at the -14 position of intron 5 of the EPCAM gene. Algorithms that predict the impact of sequence changes on splicing indicate that this change results in the creation of a splice acceptor site, which is predicted to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in multiple individuals with congenital tufting enteropathy in the homozygous and compound heterozygous state (PMID: 23462293, 24142340, 26684320, 27848944, 28701297, 30461124). This variant has a maximum subpopulation frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). In summary, this variant meets criteria to be classified as pathogenic with respect to congenital tufting enteropathy and of uncertain significance with respect to Lynch syndrome since the evidence currently available is insufficient to determine the clinical significance of this variant with respect to Lynch syndrome.

In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 34426522, 33195669, 24142340, 36457962, 23462293, 34198699, 29978187, 36451688, 26684320, 30461124, 33029133, 37554749, 27848944, 28701297, 33567694, 35261632)

The EPCAM c.556-14A>G variant is predicted to interfere with splicing. This variant has been reported in the homozygous and compound heterozygous state in patients with congenital tufting enteropathy (Schnell et al. 2013. PubMed ID: 23462293; Salomon et al. 2013. PubMed ID: 24142340; Bodian et al. 2017. PubMed ID: 28701297; Ayyıldız Civan et al. 2021. PubMed ID: 34198699) and in at least one study it was found to be associated with milder outcomes (Salomon et al. 2013. PubMed ID: 24142340). Transcript analysis found this variant results in abnormal splicing (Salomon et al. 2013. PubMed ID: 24142340) and immunostaining found it results in a lack of cell surface expression (Schnell et al. 2013. PubMed ID: 23462293). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD and has been interpreted as pathogenic/likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/157603/). This variant is interpreted as pathogenic.