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In our study, six unrelated Tunisian infants with PFIC suspicion were the subject of a panel\u2013target sequencing followed by an exhaustive bioinformatic and modeling investigations. Results revealed five disease\u2010causative variants including known ones: (the p.Asp482Gly and p.Tyr354 * in the <jats:italic>ABCB11<\/jats:italic> gene and the p.Arg446 * in the <jats:italic>ABCC2<\/jats:italic> gene), a novel p.Ala98Cys variant in the <jats:italic>ATP\u2010binding cassette subfamily G member 5<\/jats:italic> (<jats:italic>ABCG5)<\/jats:italic> gene and a first homozygous description of the p.Gln312His in the <jats:italic>ABCB11<\/jats:italic> gene. The p.Gln312His disrupts the interaction pattern of the bile salt export pump as well as the flexibility of the second intracellular loop domain harboring this residue. As for the p.Ala98Cys, it modulates both the interactions within the first nucleotide\u2010binding domain of the bile transporter and its accessibility. Two additional potentially modifier variants in cholestasis\u2010associated genes were retained based on their pathogenicity (p.Gly758Val in the <jats:italic>ABCC2<\/jats:italic> gene) and functionality (p.Asp19His in the <jats:italic>ABCG8<\/jats:italic> gene). Molecular findings allowed a PFIC2 diagnosis in five patients and an unexpected diagnosis of sisterolemia in one case. The absence of genotype\/phenotype correlation suggests the implication of environmental and epigenetic factors as well as modifier variants involved directly or indirectly in the bile composition, which could explain the cholestasis phenotypic variability.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ahg.12542","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T15:06:57Z","timestamp":1702912017000},"page":"194-211","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Molecular and computational characterization of ABCB11 and ABCG5 variants in Tunisian patients with neonatal\/infantile low\u2010GGT intrahepatic cholestasis: Genetic diagnosis and genotype\u2013phenotype correlation 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