VCV000013697.60 - ClinVar

NM_000443.4(ABCB4):c.1769G>A (p.Arg590Gln)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(11); Benign(1); Likely benign(3)

15 out of 18 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000443.4(ABCB4):c.1769G>A (p.Arg590Gln)

Variation ID: 13697 Accession: VCV000013697.60

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q21.12 7: 87431528 (GRCh38) [ NCBI UCSC ] 7: 87060844 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 2, 2016	Jan 11, 2026	Jul 13, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000443.4:c.1769G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000434.1:p.Arg590Gln	missense
NM_018849.3:c.1769G>A	NP_061337.1:p.Arg590Gln	missense
NM_018850.3:c.1769G>A	NP_061338.1:p.Arg590Gln	missense
NC_000007.14:g.87431528C>T
NC_000007.13:g.87060844C>T
NG_007118.2:g.53905G>A
	P21439:p.Arg590Gln

... more HGVS ... less HGVS

Protein change

R590Q

Other names

Canonical SPDI

NC_000007.14:87431527:C:T

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00439 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00418

1000 Genomes Project 0.00439

1000 Genomes Project 30x 0.00453

The Genome Aggregation Database (gnomAD) 0.00598

The Genome Aggregation Database (gnomAD) 0.00625

Trans-Omics for Precision Medicine (TOPMed) 0.00663

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00784

Links

ClinGen: CA123370 UniProtKB: P21439#VAR_043095 OMIM: 171060.0012 dbSNP: rs45575636 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ABCB4		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1134	1253

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cholestasis, intrahepatic, of pregnancy, 3	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	Mar 5, 2018	RCV000014696.40
Low phospholipid associated cholelithiasis	Uncertain significance (2)	criteria provided, single submitter	Mar 5, 2018	RCV000033067.26
not specified	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	Mar 4, 2025	RCV000249752.15
not provided	Conflicting classifications of pathogenicity (5)	criteria provided, conflicting classifications	Jul 13, 2025	RCV000723739.47
Progressive familial intrahepatic cholestasis type 3	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Feb 7, 2022	RCV000662150.7
Progressive familial intrahepatic cholestasis type 1	Uncertain significance (1)	criteria provided, single submitter	May 28, 2019	RCV000987909.2
ABCB4-related disorder	not provided (1)	no classification provided	-	RCV004545729.2
Cholestasis, intrahepatic, of pregnancy, 3 Low phospholipid associated cholelithiasis Progressive familial intrahepatic cholestasis type 3	Uncertain significance (1)	criteria provided, single submitter	Jun 6, 2024	RCV005042052.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	NOT SPECIFIED	PreventionGenetics, part of Exact Sciences Accession: SCV000304284.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (May 28, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Progressive familial intrahepatic cholestasis type 1	Mendelics Accession: SCV001137402.1 First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Benign (Apr 27, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Cholestasis, intrahepatic, of pregnancy, 3	Illumina Laboratory Services, Illumina Accession: SCV001319987.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 17726488 Comment: show This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (May 03, 2022) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002548022.1 First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022	Publications: PubMed (4) PubMed: 18482588‚ 21119540‚ 28733223‚ 31538484 Comment: show Variant summary: ABCB4 c.1769G>A (p.Arg590Gln) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of 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 0.0045 in 251094 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 2.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis phenotype (0.0022), strongly suggesting that the variant is benign. c.1769G>A has been reported in the literature among individuals with ABCB4-related conditions such as Anicteric Cholestasis, low phospholipid-associated cholelithiasis (LPAC), Progressive familial intrahepatic cholestasis (example, Ziol_2008, Tuan Huynh_2019, Colombo_2011, Droge_2017). These data do not allow any conclusion about variant significance. At-least one co-occurrence in cis with another presumably pathogenic variant(s) has been reported (Colombo_2011, ABCB4 c.2284G>T, p.G762X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign/Likely Benign, n=2; VUS, n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Nov 21, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004224026.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (22) PubMed: 17726488‚ 18083082‚ 18482588‚ 19018976‚ 19261551‚ 19584064‚ 20042859‚ 21119540‚ 22675952‚ 23533021‚ 25807286‚ 28733223‚ 28776642‚ 28924228‚ 29761167‚ 31538484‚ 32893960‚ 34942279‚ 35626323‚ 35741809‚ 35894240‚ 36277956 Comment: show BS1, BP2 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 4

Uncertain significance (Jun 06, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Low phospholipid associated cholelithiasis Progressive familial intrahepatic cholestasis type 3 Cholestasis, intrahepatic, of pregnancy, 3 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Fulgent Genetics, Fulgent Genetics Accession: SCV005674285.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Mar 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not specified	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004025143.2 First in ClinVar: Aug 19, 2023 Last updated: Mar 11, 2025	Publications: PubMed (3) PubMed: 18482588‚ 21119540‚ 35894240 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Mar 05, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Progressive familial intrahepatic cholestasis type 3	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000784493.3 First in ClinVar: Jul 13, 2018 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: inherited Affected status: no more Observation 1 Collection method: clinical testing Allele origin: inherited Affected status: no Number of individuals with the variant: 1 Age: 30-39 years Sex: female Geographic origin: Iran

Uncertain significance (Mar 05, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cholestasis, intrahepatic, of pregnancy, 3	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000784494.3 First in ClinVar: Oct 21, 2017 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: inherited Affected status: no more Observation 1 Collection method: clinical testing Allele origin: inherited Affected status: no Number of individuals with the variant: 1 Age: 30-39 years Sex: female Geographic origin: Iran

Uncertain significance (Mar 05, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cholecystitis	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000784495.3 First in ClinVar: Oct 21, 2017 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: inherited Affected status: no more Observation 1 Collection method: clinical testing Allele origin: inherited Affected status: no Number of individuals with the variant: 1 Age: 30-39 years Sex: female Geographic origin: Iran

Likely benign (Feb 07, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	progressive familial intrahepatic cholestasis type 3	Department of Pathology and Laboratory Medicine, Sinai Health System Accession: SCV005920625.1 First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025	Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

Likely benign (Jan 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV001962060.30 First in ClinVar: Oct 08, 2021 Last updated: Jan 11, 2026	Comment: show ABCB4: BS2 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 5

Uncertain significance (Jan 31, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002115634.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 25, 2025	Publications: PubMed (4) PubMed: 18482588‚ 21119540‚ 28733223‚ 31538484 Comment: show This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 590 of the ABCB4 protein (p.Arg590Gln). This variant is present in population databases (rs45575636, gnomAD 0.7%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of ABCB4-related conditions (PMID: 18482588, 21119540, 28733223, 31538484). ClinVar contains an entry for this variant (Variation ID: 13697). 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 ABCB4 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Apr 10, 2018) C Contributing to aggregate classification	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	not provided	Eurofins Ntd Llc (ga) Accession: SCV000226227.6 First in ClinVar: Jun 29, 2015 Last updated: Apr 13, 2025	Publications: PubMed (5) PubMed: 17726488‚ 18482588‚ 19584064‚ 23533021‚ 25807286 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCB4 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 48 Zygosity: Homozygote, Single Heterozygote Sex: mixed

Uncertain significance (Jul 13, 2025) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000490387.5 First in ClinVar: Dec 06, 2016 Last updated: Jul 19, 2025	Comment: show Reported in association with ABCB4-related disorders in several individuals who were heterozygous for R590Q alone, homozygous for R590Q, or heterozygous for R590Q and another variant in the ABCB4 gene (PMID: 18482588, 17726488, 21119540, 23533021, 26324191, 35626323, 35894240, 36982896, Lourembam-2021[CaseReport]); 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: 20981092, 22995991, 26324191, 35460704, 35288833, 18083082, 27825922, 31127640, 22675952, 25882097, 21119540, 23533021, 25807286, 28776642, 28924228, 28587926, 28765628, 27936482, 19584064, 29761167, 28733223, 31538484, 32893960, Jarasvaraparn-2021[CaseReport], Lourembam-2021[CaseReport], 34662886, 35894240, 34942279, 35626323, 36982896, 19261551, 19018976, 17726488, 18482588) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Oct 01, 2009) N Not contributing to aggregate classification	no assertion criteria provided	CHOLESTASIS, INTRAHEPATIC, OF PREGNANCY, 3	OMIM Accession: SCV000034951.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2017	Publications: PubMed (2) PubMed: 18482588‚ 19584064 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In 2 of 50 French women with intrahepatic cholestasis of pregnancy (ICP3; 614972), Bacq et al. (2009) identified a homozygous 1769G-A transition in exon 15 … (more) In 2 of 50 French women with intrahepatic cholestasis of pregnancy (ICP3; 614972), Bacq et al. (2009) identified a homozygous 1769G-A transition in exon 15 of the ABCB4 gene, resulting in an arg590-to-gln (R590Q) substitution in the nucleotide-binding domain. Three additional women with ICP were heterozygous for the R590Q mutation, as was 1 of 214 control chromosomes. The allelic frequency was significantly different between ICP patients and controls (7% vs 0.5%, respectively), yielding an odds ratio of 16.03. Haplotype analysis indicated a founder effect. Ziol et al. (2008) identified a heterozygous R590Q substitution in 3 unrelated women with anicteric cholestasis. Two had cholelithiasis at ages 18 and 51 years, respectively. One developed symptoms after taking oral contraceptives (OCIC; see 614972) and the other had recurrence of symptoms after cholecystectomy (GBD1; 600803). A third woman with the mutation was asymptomatic, but was studied because of increased liver enzymes. Ziol et al. (2008) noted that the R590Q substitution was also found in 4 controls (3%), raising questions about its pathogenicity. (less)

Pathogenic (Oct 01, 2009) N Not contributing to aggregate classification	no assertion criteria provided	GALLBLADDER DISEASE 1	OMIM Accession: SCV000056847.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2017	Publications: PubMed (2) PubMed: 18482588‚ 19584064 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In 2 of 50 French women with intrahepatic cholestasis of pregnancy (ICP3; 614972), Bacq et al. (2009) identified a homozygous 1769G-A transition in exon 15 … (more) In 2 of 50 French women with intrahepatic cholestasis of pregnancy (ICP3; 614972), Bacq et al. (2009) identified a homozygous 1769G-A transition in exon 15 of the ABCB4 gene, resulting in an arg590-to-gln (R590Q) substitution in the nucleotide-binding domain. Three additional women with ICP were heterozygous for the R590Q mutation, as was 1 of 214 control chromosomes. The allelic frequency was significantly different between ICP patients and controls (7% vs 0.5%, respectively), yielding an odds ratio of 16.03. Haplotype analysis indicated a founder effect. Ziol et al. (2008) identified a heterozygous R590Q substitution in 3 unrelated women with anicteric cholestasis. Two had cholelithiasis at ages 18 and 51 years, respectively. One developed symptoms after taking oral contraceptives (OCIC; see 614972) and the other had recurrence of symptoms after cholecystectomy (GBD1; 600803). A third woman with the mutation was asymptomatic, but was studied because of increased liver enzymes. Ziol et al. (2008) noted that the R590Q substitution was also found in 4 controls (3%), raising questions about its pathogenicity. (less)

not provided (-) N Not contributing to aggregate classification	no classification provided	ABCB4-related disorders	GenomeConnect, ClinGen Accession: SCV000840292.2 First in ClinVar: Oct 14, 2018 Last updated: Apr 13, 2025	Comment: show GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Observation: 1 Collection method: phenotyping only Allele origin: unknown Affected status: unknown more Observation 1 Collection method: phenotyping only Allele origin: unknown Affected status: unknown Clinical Features: Maternal teratogenic exposure (present) , Abnormality of the placenta (present) , Short stature (present) , Delayed puberty (present) , Myopia (present) , Hyperacusis (present) , Memory impairment (present) , Generalized hypotonia (present) , Abnormality of coordination (present) , Depressivity (present) , Anxiety (present) , Stereotypy (present) , Increased susceptibility to fractures (present) , Joint hypermobility (present) , Abnormality of the curvature of the vertebral column (present) , Abnormality of the musculature of the limbs (present) , Abnormality of muscle physiology (present) , Hypercholesterolemia (present) , Syncope (present) , Cardiomyopathy (present) , Asthma (present) , Abnormality of the intestine (present) , Abnormality of the liver (present) , Abnormality of the stomach (present) , Abnormality of esophagus morphology (present) , Feeding difficulties (present) , Abnormality of reproductive system physiology (present) , Abnormality of the female genitalia (present) , Recurrent infections (present) Indication for testing: Diagnostic, Cardiomyopathy Test name: Gene Panel Sequencing Age: 40-49 years Sex: female Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2017-12-14 Testing laboratory interpretation: Uncertain significance

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Comment:

Variant summary: ABCB4 c.1769G>A (p.Arg590Gln) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of 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 0.0045 in 251094 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 2.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis phenotype (0.0022), strongly suggesting that the variant is benign. c.1769G>A has been reported in the literature among individuals with ABCB4-related conditions such as Anicteric Cholestasis, low phospholipid-associated cholelithiasis (LPAC), Progressive familial intrahepatic cholestasis (example, Ziol_2008, Tuan Huynh_2019, Colombo_2011, Droge_2017). These data do not allow any conclusion about variant significance. At-least one co-occurrence in cis with another presumably pathogenic variant(s) has been reported (Colombo_2011, ABCB4 c.2284G>T, p.G762X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign/Likely Benign, n=2; VUS, n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 590 of the ABCB4 protein (p.Arg590Gln). This variant is present in population databases (rs45575636, gnomAD 0.7%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of ABCB4-related conditions (PMID: 18482588, 21119540, 28733223, 31538484). ClinVar contains an entry for this variant (Variation ID: 13697). 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 ABCB4 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

Reported in association with ABCB4-related disorders in several individuals who were heterozygous for R590Q alone, homozygous for R590Q, or heterozygous for R590Q and another variant in the ABCB4 gene (PMID: 18482588, 17726488, 21119540, 23533021, 26324191, 35626323, 35894240, 36982896, Lourembam-2021[CaseReport]); 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: 20981092, 22995991, 26324191, 35460704, 35288833, 18083082, 27825922, 31127640, 22675952, 25882097, 21119540, 23533021, 25807286, 28776642, 28924228, 28587926, 28765628, 27936482, 19584064, 29761167, 28733223, 31538484, 32893960, Jarasvaraparn-2021[CaseReport], Lourembam-2021[CaseReport], 34662886, 35894240, 34942279, 35626323, 36982896, 19261551, 19018976, 17726488, 18482588)

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A BCB4 variant is associated with hepatobiliary MR abnormalities in people with low-phospholipid-associated cholelithiasis syndrome.	Biyoukar M	JHEP reports : innovation in hepatology	2022	PMID: 36277956
Clinical phenotype of adult-onset liver disease in patients with variants in ABCB4, ABCB11, and ATP8B1.	Nayagam JS	Hepatology communications	2022	PMID: 35894240
Genetic Analysis of ABCB4 Mutations and Variants Related to the Pathogenesis and Pathophysiology of Low Phospholipid-Associated Cholelithiasis.	Wang HH	Genes	2022	PMID: 35741809
Targeted-Capture Next-Generation Sequencing in Diagnosis Approach of Pediatric Cholestasis.	Almes M	Diagnostics (Basel, Switzerland)	2022	PMID: 35626323
Heterozygous mutations of ATP8B1, ABCB11 and ABCB4 cause mild forms of Progressive Familial Intrahepatic Cholestasis in a pediatric cohort.	Mínguez Rodríguez B	Gastroenterologia y hepatologia	2022	PMID: 34942279
Carriers of ABCB4 gene variants show a mild clinical course, but impaired quality of life and limited risk for cholangiocarcinoma.	de Vries E	Liver international : official journal of the International Association for the Study of the Liver	2020	PMID: 32893960
Clinical characteristics and genetic profiles of young and adult patients with cholestatic liver disease.	Huynh MT	Revista espanola de enfermedades digestivas	2019	PMID: 31538484
Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset.	Schatz SB	Hepatology communications	2018	PMID: 29761167
Diagnosis of monogenic liver diseases in childhood by next-generation sequencing.	Stalke A	Clinical genetics	2018	PMID: 28776642
An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy.	Dixon PH	Scientific reports	2017	PMID: 28924228
Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants.	Dröge C	Journal of hepatology	2017	PMID: 28733223
Large-scale whole-genome sequencing of the Icelandic population.	Gudbjartsson DF	Nature genetics	2015	PMID: 25807286
Genotype-phenotype relationships in the low-phospholipid-associated cholelithiasis syndrome: a study of 156 consecutive patients.	Poupon R	Hepatology (Baltimore, Md.)	2013	PMID: 23533021
Severe hepatocellular dysfunction in obstetric cholestasis related to combined genetic variation in hepatobiliary transporters.	Zimmer V	Clinical and experimental obstetrics & gynecology	2012	PMID: 22675952
Clinical features and genotype-phenotype correlations in children with progressive familial intrahepatic cholestasis type 3 related to ABCB4 mutations.	Colombo C	Journal of pediatric gastroenterology and nutrition	2011	PMID: 21119540
Genetics of cholestatic liver disease in 2010.	Karlsen TH	Current opinion in gastroenterology	2010	PMID: 20042859
ABCB4 gene mutations and single-nucleotide polymorphisms in women with intrahepatic cholestasis of pregnancy.	Bacq Y	Journal of medical genetics	2009	PMID: 19584064
A new splicing site mutation of the ABCB4 gene in intrahepatic cholestasis of pregnancy with raised serum gamma-GT.	Tavian D	Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver	2009	PMID: 19261551
ABCB4 sequence variations in young adults with cholesterol gallstone disease.	Nakken KE	Liver international : official journal of the International Association for the Study of the Liver	2009	PMID: 19018976
ABCB4 heterozygous gene mutations associated with fibrosing cholestatic liver disease in adults.	Ziol M	Gastroenterology	2008	PMID: 18482588
Hepatobiliary phospholipid transporter ABCB4, MDR3 gene variants in a large cohort of Italian women with intrahepatic cholestasis of pregnancy.	Floreani A	Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver	2008	PMID: 18083082
Molecular characterization and structural implications of 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3 (PFIC3).	Degiorgio D	European journal of human genetics : EJHG	2007	PMID: 17726488
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCB4	-	-	-	-
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Text-mined citations for rs45575636 ...

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Record last updated Jan 11, 2026