The p.Arg575Ter variant in ABCB11 has been reported in many individuals with BSEP deficiency (PMID: 9806540, 17452236, 14988830, 18395098, 25847299, 28733223, 37168916), and has been identified in 0.05% (29/59856) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs72549401). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 6589) and has been interpreted as pathogenic by Invitae and OMIM. Of the affected individuals, five were compound heterozygotes that carried a reported pathogenic or likely pathogenic variant in trans or with unknown phase, which increases the likelihood that the p.Arg575Ter variant is pathogenic (Variation ID: 501601, 595313; PMID: 17452236, 18395098). This nonsense variant leads to a premature termination codon at position 575, which is predicted to lead to a truncated or absent protein. Computational tools predict a splicing impact of in-frame exon skipping, though this information is not predictive enough to rule out pathogenicity. Loss of function of the ABCB11 gene is an established disease mechanism in autosomal recessive BSEP deficiency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive BSEP deficiency. ACMG/AMP Criteria applied: PVS1_strong, PM3_strong (Richards 2015).

The c.1723C>T variant in ABCB11 is a nonsense variant predicted to introduce a stop codon at amino acid 575. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 18395098). Given the available evidence, this variant is classified as Pathogenic.

ACMG categories: PVS1,PS4,PM2_sup,PM3_sup

Variant summary: ABCB11 c.1723C>T (p.Arg575X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-05 in 248568 control chromosomes. This frequency is not significantly higher than estimated for disease-causing variants in ABCB11, allowing no conclusion about variant significance. c.1723C>T has been observed in individual(s) affected with Progressive familial intrahepatic cholestasis type 1 (Strautnieks_1998). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 9806540). ClinVar contains an entry for this variant (Variation ID: 6589). Based on the evidence outlined above, the variant was classified as pathogenic.

ClinVar contains an entry for this variant (Variation ID: 6589). This sequence change creates a premature translational stop signal (p.Arg575*) in the ABCB11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCB11 are known to be pathogenic (PMID: 18395098, 20232290). This variant is present in population databases (rs72549401, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with progressive familial intrahepatic cholestasis (PMID: 9806540). For these reasons, this variant has been classified as Pathogenic.

ABCB11 p.Arg575Ter (c.1723C>T) is a nonsense variant that introduces a premature stop codon at amino acid position 575, creating a truncated protein that is predicted to undergo nonsense-mediated mRNA decay. This variant has been observed in at least one proband with an ABCB11-related disorder (PMID:38341604;37762919;37168916;35780807;28733223;12717091;25847299;17452236;18395098;9806540;21490445). The variant was found to segregate with disease in at least one affected family (PMID:21490445). It is absent or not present at a significant frequency in gnomAD. In conclusion, we classify ABCB11 p.Arg575Ter (c.1723C>T) as a pathogenic variant.

The ABCB11 c.1723C>T variant is predicted to result in premature protein termination (p.Arg575*). This variant has been reported with a second ABCB11 variant or in the homozygous state in individuals with familial progressive intrahepatic cholestasis (Strautnieks et al 1998. PubMed ID: 9806540; Schiemann et al. 2007. PubMed ID: 17452236; Table S3, Hertel et al. 2021. PubMed ID: 34016879) or benign recurrent intrahepatic cholestasis (Kato et al. 2023. PubMed ID: 37762919). This variant is reported in 0.026% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in ABCB11 are expected to be pathogenic. This variant is interpreted as pathogenic.