Submissions for variant NM_002354.3(EPCAM):c.491+1G>A

gnomAD frequency: 0.00002  dbSNP: rs606231203

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV004018623	SCV004865654	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-06	criteria provided, single submitter	clinical testing	The c.491+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 4 of the EPCAM gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function. Based on data from gnomAD, the A allele has an overall frequency of 0.0056% (14/251,214) total alleles studied. The highest observed frequency was 0.03% (11/34,570) of Latino alleles. This alteration was reported homozygous or compound heterozygous with a second mutation in EPCAM in multiple patients with failure to thrive, diarrhea, vomiting, and endoscopic duodenal biopsies with characteristic histology consistent with congenital tufting enteropathy (Sivagnanam, 2008; Ko, 2010; Fang, 2020). This nucleotide position is highly conserved in available vertebrate species. Reverse-transcription polymerase chain reaction of duodenal tissue demonstrated a novel alternative splice form with deletion of exon 4 (Sivagnanam, 2008). Mutant mice with universal Epcam exon 4 deletion showed widespread epithelial dysplasia, intestinal failure, and limited life spans with a dramatic lack of weight gain compared with wildtype mice (Mueller, 2014). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.
Aleixo Muise Laboratory, Hospital For Sick Children	RCV000013609	SCV005088115	pathogenic	Congenital diarrhea 5 with tufting enteropathy	2024-07-05	criteria provided, single submitter	research	PVS1;PM2;PM3;PP1;PP3;PP4
OMIM	RCV000013609	SCV000033856	pathogenic	Congenital diarrhea 5 with tufting enteropathy	2013-07-01	no assertion criteria provided	literature only
Laboratory for Genotyping Development, RIKEN	RCV003162250	SCV002758532	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV004794337	SCV005414414	not provided	not provided		no assertion provided	research