ClinVar Genomic variation as it relates to human health

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

Variant summary: ABCB11 c.2494C>T (p.Arg832Cys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248548 control chromosomes. c.2494C>T has been reported in the literature as biallelic homozygous or compound heterozygous and even one case involving paternal isodisomy of chromosome 2 in individuals affected with features of Familial Intrahepatic Cholestasis (example, PMID: 33915153, 19101985, 22364601, 18395098). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The missense c.2494C>T (p.Arg832Cys) variant in ABCB11 has been reported in homozygous state in individuals affected with intrahepatic cholestasis (Isabella Giovannoni et al.,2012) . Experimental studies have shown that this missense had only a mild effect on mRNA (Byrne JA et al,2009). This variant is reported with the allele frequency 0.0007% in the gnomad and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic/Likely_pathogenic. The amino acid Arg at position 832 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg832Cys in ABCB11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 832 of the ABCB11 protein (p.Arg832Cys). This variant is present in population databases (rs772294884, gnomAD 0.002%). This missense change has been observed in individuals with progressive familial intrahepatic cholestasis and benign recurrent intrahepatic cholestasis (PMID: 16641580, 18395098, 27114171, 28733223). ClinVar contains an entry for this variant (Variation ID: 501603). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCB11 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 19133130, 19101985, 16641580, 28733223, 18395098, 22364601, 25847799, 31400129, 27114171, 33915153)