ClinVar Miner

Submissions for variant NM_003742.4(ABCB11):c.3457C>T (p.Arg1153Cys)

gnomAD frequency: 0.00004  dbSNP: rs72549395
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000333806 SCV000342922 pathogenic not provided 2017-11-14 criteria provided, single submitter clinical testing
Baylor Genetics RCV000984920 SCV001521272 likely pathogenic Progressive familial intrahepatic cholestasis type 2 2020-03-04 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae RCV000333806 SCV001592648 pathogenic not provided 2023-09-11 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1153 amino acid residue in ABCB11. Other variant(s) that disrupt this residue have been observed in individuals with ABCB11-related conditions (PMID: 18395098, 26678486), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects ABCB11 function (PMID: 12370274, 18798335). 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. ClinVar contains an entry for this variant (Variation ID: 288726). This missense change has been observed in individuals with familial intrahepatic cholestasis (PMID: 9806540, 18395098, 20232290, 26678486, 27050426). This variant is present in population databases (rs72549395, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1153 of the ABCB11 protein (p.Arg1153Cys).
GeneDx RCV000333806 SCV001771733 pathogenic not provided 2021-07-01 criteria provided, single submitter clinical testing Published functional studies demonstrate this variant results in impaired transport activity and protein expression as compared to wild-type (Ho et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9806540, 12370274, 18798335, 10579978, 28733223, 32289814, 19101985, 33915153, 20683201, 20422495, 18395098, 27050426, 20232290, 26678486, 25085279, 28119944, 26382629, 27535533, 17241866, 20010382, 17947449)
Revvity Omics, Revvity RCV000333806 SCV002020997 likely pathogenic not provided 2021-03-18 criteria provided, single submitter clinical testing
Baylor Genetics RCV003463773 SCV004196312 pathogenic Benign recurrent intrahepatic cholestasis type 2 2023-10-22 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003930155 SCV004746130 pathogenic ABCB11-related disorder 2023-12-01 criteria provided, single submitter clinical testing The ABCB11 c.3457C>T variant is predicted to result in the amino acid substitution p.Arg1153Cys. This variant has been reported as causative for intrahepatic cholestasis (Strautnieks et al. 1998. PubMed ID: 9806540; Al-Hussaini et al. 2021. PubMed ID: 33915153; Bakır et al. 2021. PubMed ID: 34961929). Functional studies have shown that the p.Arg1153Cys substitutions prevents proper protein localization and function (Wang et al. 2002. PubMed ID: 12370274; Byrne et al. 2009. PubMed ID: 19101985). An alternate substitution of this amino acid (p.Arg1153His) has also been reported in individuals with intrahepatic cholestasis (Strautnieks et al. 2008. PubMed ID: 18395098). This variant is reported in 0.0041% of alleles in individuals of African descent in gnomAD. Given the evidence, we interpret c.3457C>T (p.Arg1153Cys) as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000984920 SCV004801254 pathogenic Progressive familial intrahepatic cholestasis type 2 2024-03-14 criteria provided, single submitter research
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City RCV000984920 SCV001132829 pathogenic Progressive familial intrahepatic cholestasis type 2 2019-01-29 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000333806 SCV001929386 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000333806 SCV001952155 pathogenic not provided no assertion criteria provided clinical testing
Natera, Inc. RCV000984920 SCV002077884 pathogenic Progressive familial intrahepatic cholestasis type 2 2020-08-18 no assertion criteria provided clinical testing

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