Submissions for variant NM_003742.4(ABCB11):c.1460G>A (p.Arg487His)

gnomAD frequency: 0.00013  dbSNP: rs188824058

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000396656	SCV000344575	likely pathogenic	not provided	2017-10-03	criteria provided, single submitter	clinical testing
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000761414	SCV000891472	likely pathogenic	Progressive familial intrahepatic cholestasis type 2	2023-11-30	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV000763465	SCV000894242	likely pathogenic	Benign recurrent intrahepatic cholestasis type 2; Progressive familial intrahepatic cholestasis type 2	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000396656	SCV000959798	pathogenic	not provided	2022-09-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 487 of the ABCB11 protein (p.Arg487His). This variant is present in population databases (rs188824058, gnomAD 0.02%). This missense change has been observed in individual(s) with chronic cholestasis (PMID: 12717091, 27050426). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 290081). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg487 amino acid residue in ABCB11. Other variant(s) that disrupt this residue have been observed in individuals with ABCB11-related conditions (PMID: 12717091, 18395098, 27050426), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001805001	SCV002051385	pathogenic	Progressive familial intrahepatic cholestasis	2021-12-27	criteria provided, single submitter	clinical testing	Variant summary: ABCB11 c.1460G>A (p.Arg487His) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) 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 9.3e-05 in 247784 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCB11 causing Familial Intrahepatic Cholestasis (9.3e-05 vs 0.0022), allowing no conclusion about variant significance. c.1460G>A has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Familial Intrahepatic Cholestasis (example, Goto_2003, Li Wang_2016, Togawa_2016, Liu_2018, Ting Li_2020). 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 (likely pathogenic, n=3; VUS, n=1). At-least one submitter cites overlapping but not identical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000396656	SCV002525754	pathogenic	not provided	2021-12-14	criteria provided, single submitter	clinical testing	PP3, PM2, PM3_strong, PM5, PS3_moderate
PreventionGenetics, part of Exact Sciences	RCV003401274	SCV004119085	likely pathogenic	ABCB11-related disorder	2022-10-31	criteria provided, single submitter	clinical testing	The ABCB11 c.1460G>A variant is predicted to result in the amino acid substitution p.Arg487His. This variant has been reported in the compound heterozygous state with other pathogenic ABCB11 variants in multiple individuals with autosomal recessive familial progressive intrahepatic cholestasis (Goto et al. 2003. PubMed ID: 12717091; Dröge et al. 2017. PubMed ID: 28733223; Turro et al. 2020. PubMed ID: 32581362; Li et al. 2020. PubMed ID: 32808743) Two other missense changes at the same amino acid position have also been reported in individuals with ABCB11-related disorders (p.Arg487Cys, p.Arg487Pro; Human Gene Mutation Database). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-169828535-C-T). This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV003469246	SCV004192482	pathogenic	Benign recurrent intrahepatic cholestasis type 2	2024-03-25	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000396656	SCV004238401	likely pathogenic	not provided	2023-02-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000761414	SCV004801550	pathogenic	Progressive familial intrahepatic cholestasis type 2	2020-04-28	criteria provided, single submitter	clinical testing	The ABCB11 c.1460G>A p.(Arg487His) missense has been identified in individuals with a phenotype consistent with progressive familial intrahepatic cholestasis (Goto et al. 2003; Strautnieks et al. 2008; Smith Jericho et al. 2015; Togawa et al. 2016; Wang et al. 2016; Dröge et al. 2017; Nakano et al. 2019; Liu et al. 2020). The p.(Arg487His) variant is reported at a frequency of 0.0001726 in the European (non-Finnish) population of the Genome Aggregation Database (version 2.1.1). The variant is located within the conserved nucleotide binding domain of the protein (Wang et al. 2020). Ectopic overexpression of the p.(Arg487His) variant in the liver cell line HepG2, resulted in mislocalisation within the endoplasmic reticulum (ER) when compared to the wild type control which localized to the bile canaliculus (Nakano et al. 2019). Expression studies in HEK293 cells indicated that whilst the majority of the mutant protein was retained in the ER, the portion of the p.(Arg487His) variant protein which did localize to the cell membrane, retained ABCB11 ATP-dependent transporter activity (Nakano et al. 2019). Based on the available evidence the c.1460G>A p.(Arg487His) variant is classified as pathogenic for progressive familial intrahepatic cholestasis.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003929	SCV001161903	likely pathogenic	Cholestasis, intrahepatic, of pregnancy, 3		no assertion criteria provided	research