Submissions for variant NM_000213.5(ITGB4):c.2254+1G>T

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002306133	SCV002599860	pathogenic	not provided	2022-11-04	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Reported with another variant in a patient with epidermolysis bullosa with pyloric atresia, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Wang et al., 2020); This variant is associated with the following publications: (PMID: 32506467, 31851393)
Invitae	RCV002306133	SCV004529236	likely pathogenic	not provided	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 19 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 not present in population databases (gnomAD no frequency). 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: 1723026). 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.