Submissions for variant NM_000213.5(ITGB4):c.2550+1G>A

dbSNP: rs545619665

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779230	SCV000915780	uncertain significance	Junctional epidermolysis bullosa with pyloric atresia	2017-12-15	criteria provided, single submitter	clinical testing	The ITGB4 c.2550+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance, but suspicious for pathogenicity for epidermolysis bulllosa with pyloric atresia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003688883	SCV004425658	likely pathogenic	not provided	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 21 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 (rs545619665, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ITGB4-related conditions. ClinVar contains an entry for this variant (Variation ID: 632288). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Molecular Genetics Department, Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology	RCV000779230	SCV004801826	likely pathogenic	Junctional epidermolysis bullosa with pyloric atresia		criteria provided, single submitter	clinical testing	A previously undescribed nucleotide variant creates an alteration of the canonical splice site c.2550+1G>A in the ITGB4 gene. The variant was observed in homozygous state in an individual affected with epidermolysis bullosa and pyloric atreasia. Homozygous and compound heterozygous variants are reported in patients with Epidermolysis bullosa, junctional 5B, with pyloric atresia, 226730. The variant is present in gnomAD population database at low frequency (1/249182 chromosomes, no homozygotes). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as likely pathogenic.