Submissions for variant NM_003742.4(ABCB11):c.77-2A>G

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002810390	SCV003197577	likely pathogenic	not provided	2022-07-12	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 2 of the ABCB11 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 ABCB11 are known to be pathogenic (PMID: 18395098, 20232290). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ABCB11-related conditions. 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV005254134	SCV005907585	likely pathogenic	Progressive familial intrahepatic cholestasis type 2	2025-02-04	criteria provided, single submitter	curation	The c.77-2A>G variant in ABCB11 has not been previously reported in the literature in individuals with BSEP deficiency, but has been identified in 0.002% (1/44538) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 1998337) and has been interpreted as likely pathogenic by Invitae. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the ABCB11 gene is an established disease mechanism in autosomal recessive BSEP deficiency. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for BSEP deficiency. ACMG/AMP Criteria applied: PVS1, PM2_supporting (Richards 2015).