2-168972025-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_003742.4(ABCB11):c.1460G>A(p.Arg487His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000713 in 1,612,670 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

ABCB11
NM_003742.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 3.42

Variant links:

Genes affected

ABCB11 (HGNC:42): (ATP binding cassette subfamily B member 11) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is the major canalicular bile salt export pump in man. Mutations in this gene cause a form of progressive familial intrahepatic cholestases which are a group of inherited disorders with severe cholestatic liver disease from early infancy. [provided by RefSeq, Jul 2008]

ABCB11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-168972025-C-T is Pathogenic according to our data. Variant chr2-168972025-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 290081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-168972025-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB11	NM_003742.4 link	c.1460G>A	p.Arg487His	missense_variant	Exon 14 of 28	ENST00000650372.1	NP_003733.2	O95342

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB11	ENST00000650372.1 link	c.1460G>A	p.Arg487His	missense_variant	Exon 14 of 28		NM_003742.4	ENSP00000497931.1		O95342
ABCB11	ENST00000439188.1 link	n.8G>A		non_coding_transcript_exon_variant	Exon 1 of 15	2		ENSP00000416058.1		H7C486

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00769

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000928

AC:

AN:

247784

Hom.:

AF XY:

0.0000744

AC XY:

AN XY:

134412

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.0000583

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000561

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000161

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000650

AC:

AN:

1460544

Hom.:

Cov.:

AF XY:

0.0000606

AC XY:

AN XY:

726556

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000729

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000131

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000110

Hom.:

Bravo

AF:

0.000215

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000239

AC:

ExAC

AF:

0.000116

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCB11 protein function with a positive predictive value of 80%. 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. -

Oct 03, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 14, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2, PM3_strong, PM5, PS3_moderate -

Feb 07, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Progressive familial intrahepatic cholestasis type 2

Pathogenic:3

Jan 27, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg487His variant in ABCB11 has been reported in at least seven individuals with BSEP deficiency (PMID: 12717091, 18692205, 20683201, 26858187, 28733223, 27050426, 32309332), and has been identified in 0.008% (5/59818) of Admixed chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs188824058). 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: 290081) and has been interpreted as a variant of uncertain significance by Department Of Genetics Sultan Qaboos University Hospital (Sultan Qaboos University) and as likely pathogenic/pathogenic by multiple other submitters. Of the seven affected individuals, three were compound heterozygotes that carried a reported pathogenic or likely pathogenic variant in trans, which increases the likelihood that the p.Arg487His variant is pathogenic (Variation ID: 1070887, 6596; PMID: 12717091, 28733223, 27050426). In vitro functional studies provide some evidence that the p.Arg487His variant may slightly impact protein function (PMID: 31745229). However, these types of assays may not accurately represent biological function. 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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive BSEP deficiency. ACMG/AMP Criteria applied: PM3_strong, PS3_supporting, PP3 (Richards 2015). -

Nov 30, 2023

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Apr 28, 2020

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

ABCB11-related disorder

Pathogenic:1

Oct 31, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Cholestasis, intrahepatic, of pregnancy, 3

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Benign recurrent intrahepatic cholestasis type 2

Pathogenic:1

Mar 25, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign recurrent intrahepatic cholestasis type 2;C3489789:Progressive familial intrahepatic cholestasis type 2

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Progressive familial intrahepatic cholestasis

Pathogenic:1

Dec 27, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;D

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.97

.;D

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.48

T;T

MetaSVM

Pathogenic

0.82

MutationAssessor

Benign

1.6

L;L

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.9

D;.

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0040

D;.

Polyphen

1.0

D;D

Vest4

0.85

MVP

0.93

MPC

0.70

ClinPred

0.76

GERP RS

5.9

Varity_R

0.79

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over