Submissions for variant NM_000213.5(ITGB4):c.3793+1G>A

gnomAD frequency: 0.00001  dbSNP: rs147222357

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255841	SCV000321784	pathogenic	not provided	2018-03-01	criteria provided, single submitter	clinical testing	The c.3793+1G>A: IVS30+1G>A pathogenic variant in the ITGB4 gene has been reported previously in association with EB-PA (Pulkkinen et al. 1997 Mellerio et al., 1998, Ashton et al., 2001, Varki et al., 2006, Dang et al. 2008, Lee et al. 2015). Pulkkinen et al. 1997 showed that the variant leads to the use of a cryptic splice site and results in a frameshift and the creation of a downstream STOP codon resulting in premature termination of the protein and when present in the homozygous state results in a severe phenotype (Dang et al., 2008). This splice site variant destroys the canonical splice donor site in intron 30. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.3793+1G>A: IVS30+1G>A variant was not observed in significant numbers in approximately 8600 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.3793+1G>A: IVS30+1G>A as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255841	SCV004297542	pathogenic	not provided	2023-09-19	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 30 of the ITGB4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ITGB4 are known to be pathogenic (PMID: 11328943, 16473856). This variant is present in population databases (rs147222357, gnomAD 0.002%). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 14736). Disruption of this splice site has been observed in individuals with epidermolysis bullosa (PMID: 33937469, 34046686). For these reasons, this variant has been classified as Pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000015857	SCV004807721	pathogenic	Junctional epidermolysis bullosa with pyloric atresia	2024-03-29	criteria provided, single submitter	clinical testing
OMIM	RCV000015857	SCV000036124	pathogenic	Junctional epidermolysis bullosa with pyloric atresia	1998-11-01	no assertion criteria provided	literature only