Submissions for variant NM_003742.4(ABCB11):c.2086C>T (p.Arg696Trp)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002283409	SCV002571995	uncertain significance	not specified	2023-07-28	criteria provided, single submitter	clinical testing	Variant summary: ABCB11 c.2086C>T (p.Arg696Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 177220 control chromosomes (gnomAD). c.2086C>T has been reported in the literature in compound heterozygous state in 2 children, affected with transient neonatal cholestasis and progressive familial intrahepatic cholestasis type 2 (PFIC2) (Liu_2020, Li_2020) and was also reported in heterozygous state in a child with diagnosis for PFIC2 (Hu_2014) and in cohort of patients affected with intrahepatic cholestasis of pregnancy (ICP), however without specifying the genotype of the affected individual(s) (Liu_2020). 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 publications have been ascertained in the context of this evaluation (PMID: 32808743, 24969679, 32309332, 32942997). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV003464432	SCV004214990	likely pathogenic	Benign recurrent intrahepatic cholestasis type 2	2024-02-29	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV005254050	SCV005907481	uncertain significance	Progressive familial intrahepatic cholestasis type 2	2025-01-24	criteria provided, single submitter	curation	The p.Arg696Trp variant in ABCB11 has been previously reported in three individuals with BSEP deficiency (PMID: 24969679, 32309332, 32808743), and has been identified in 0.01% (5/42198) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs376216286). 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: 1705084) and has been interpreted as a variant of uncertain significance by Women's Health and Genetics/Laboratory Corporation of America (LabCorp). Of the 3 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variant with unknown phase and 1 was a compound heterozygote that carried a variant of uncertain significance in trans, which increases the likelihood that the p.Arg696Trp variant is pathogenic (Variation ID: 290081; PMID: 32808743, 32309332). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg696Trp variant is uncertain. ACMG/AMP Criteria applied: PP3_moderate, PM2_supporting, PM3_supporting (Richards 2015).
PreventionGenetics, part of Exact Sciences	RCV003971229	SCV004784786	likely pathogenic	ABCB11-related disorder	2023-12-12	no assertion criteria provided	clinical testing	The ABCB11 c.2086C>T variant is predicted to result in the amino acid substitution p.Arg696Trp. This variant was reported in a child with intrahepatic cholestasis (Table 3, Hu et al. 2014. PubMed ID: 24969679). In addition, it was reported with a second ABCB11 variant in patients with neonatal cholestasis (Table 1, Li et al. 2020. PubMed ID: 32808743) or progressive familial intrahepatic cholestasis type 2 (Table S1, Liu et al. 2020. PubMed ID: 32309332). It was also reported in unknown zygosity in intrahepatic cholestasis of pregnancy (Table 2, Liu et al. 2020. PubMed ID: 32942997). This variant is reported in 0.017% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic.