2-168972025-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R487C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: ABCB11 NM_003742.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 3.42

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_003742.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-168972026-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2201969.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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/exons	MANE	UniProt
ABCB11	NM_003742.4	c.1460G>A	p.Arg487His	missense_variant	14/28	ENST00000650372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB11	ENST00000650372.1	c.1460G>A	p.Arg487His	missense_variant	14/28		NM_003742.4	P1
ABCB11	ENST00000439188.1	c.8G>A	p.Arg3His	missense_variant, NMD_transcript_variant	1/15	2

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152006 Hom.: 0 Cov.: 33

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: 23 AN: 247784 Hom.: 0 AF XY: 0.0000744 AC XY: 10 AN XY: 134412

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: 95 AN: 1460544 Hom.: 0 Cov.: 32 AF XY: 0.0000606 AC XY: 44 AN XY: 726556

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: 20 AN: 152126 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74368

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.: 0

Bravo AF: 0.000215

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000239 AC: 2

ExAC AF: 0.000116 AC: 14

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 14, 2021	PP3, PM2, PM3_strong, PM5, PS3_moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 23, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 07, 2023	- -

Progressive familial intrahepatic cholestasis type 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2020	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. -
Likely pathogenic, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Nov 30, 2023	- -

ABCB11-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2022

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

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

Benign recurrent intrahepatic cholestasis type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 26, 2023

- -

Benign recurrent intrahepatic cholestasis type 2;C3489789:Progressive familial intrahepatic cholestasis type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Progressive familial intrahepatic cholestasis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 27, 2021

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	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
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	D
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

Other links and lift over

dbSNP: rs188824058; hg19: chr2-169828535; COSMIC: COSV104562931; COSMIC: COSV104562931;