rs141677867

Variant names:

• chr7-87423940-G-A
• rs141677867
• NM_000443.4:c.2177C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP2 PP3_Strong PP5_Very_Strong

The NM_000443.4(ABCB4):​c.2177C>T​(p.Pro726Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P726P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ABCB4 NM_000443.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 U:1
• Conservation: PhyloP100: 9.28
• Publications: 12 publications found

Genes affected

ABCB4 (HGNC:45): (ATP binding cassette subfamily B member 4) 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 as well as antigen presentation. This gene encodes a full transporter and member of the p-glycoprotein family of membrane proteins with phosphatidylcholine as its substrate. The function of this protein has not yet been determined; however, it may involve transport of phospholipids from liver hepatocytes into bile. Alternative splicing of this gene results in several products of undetermined function. [provided by RefSeq, Jul 2008]

ABCB4 Gene-Disease associations (from GenCC):

• progressive familial intrahepatic cholestasis type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• gallbladder disease 1

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PP2: Missense variant in the ABCB4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 1.9749 (below the threshold of 3.09). Trascript score misZ: 3.5425 (above the threshold of 3.09). GenCC associations: The gene is linked to gallbladder disease 1, progressive familial intrahepatic cholestasis type 3, pancreatitis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 7-87423940-G-A is Pathogenic according to our data. Variant chr7-87423940-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 194709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB4	NM_000443.4	c.2177C>T	p.Pro726Leu	missense_variant	Exon 17 of 28	ENST00000649586.2	NP_000434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB4	ENST00000649586.2	c.2177C>T	p.Pro726Leu	missense_variant	Exon 17 of 28		NM_000443.4	ENSP00000496956.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251176 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461802 Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74286

African (AFR) AF: 0.0000241 AC: 1 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000203 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Jul 06, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has been observed as a single heterozygous variant, as homozygous variant, or with a second ABCB4 variant in patients with abnormal liver tests, cholelithias, cholestasis and/or cholangitis (Davit- Spraul et al., 2010; Poupon et al., 2013; Lin et al., 2014; Delaunay et al., 2015; Elderman et al., 2015); Published functional studies demonstrate a damaging effect as the P726L variant abolishes phosphatidylchoine secretion (Delaunay et a;., 2015; Delaunay et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); 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: 26474921, 28012258, 20422496, 28757171, 23533021, 25612754, 31589614, 33842647, 32893960, 34961929, 32917322, 35894240, 36569137)

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCB4: PM2, PM5, PS3:Moderate, PP4, PS4:Supporting

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 726 of the ABCB4 protein (p.Pro726Leu). This variant is present in population databases (rs141677867, gnomAD 0.003%). This missense change has been observed in individuals with low-phospholipid-associated cholelithiasis syndrome and/or progressive familial intrahepatic cholestasis type 3 (PMID: 20422496, 23533021, 26474921, 28733223, 29761167). ClinVar contains an entry for this variant (Variation ID: 194709). 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%. Experimental studies have shown that this missense change affects ABCB4 function (PMID: 26474921, 28012258). For these reasons, this variant has been classified as Pathogenic.

Jan 03, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Progressive familial intrahepatic cholestasis type 3 Pathogenic:3

Feb 12, 2025

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.91 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000194709 /PMID: 20422496, 23533021 /3billion dataset). The variant has been observed in at least two similarly affected unrelated individuals (3billion dataset). A different missense change at the same codon (p.Pro726Thr) has been reported to be associated with ABCB4-related disorder (PMID: 17726488). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Jan 01, 2022

Rolfs Rare Disease Consulting, Rolfs Consulting Und Verwaltungs GmbH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with intrahepatic cholestasis of pregnancy 3 (ICP-3) (MIM#614972), gallbladder disease 1 (low phospholipid-associated cholelithiasis (LPAC)) (MIM# 600803) and progressive familial intrahepatic cholestasis 3 (PFIC) (MIM#602347). (I) 0108 - This gene is associated with both recessive and dominant disease. PFIC is inherited in a recessive manner, whereas ICP-3 and LPAC can be either dominant or recessive. Biallelic variants typically demonstrate less residual protein activity, resulting in earlier onset of the condition with a more severe phenotype (OMIM, PMID: 24806754, PMID: 32376413). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 31759867). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2, v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ABC transmembrane type-1 2 domain (Uniprot). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic (ClinVar, LOVD) and has been observed in several heterozygous and compound heterozygous individuals with low phospholipid-associated cholelithiasis (LPAC) or intrahepatic cholestasis of pregnancy (IPC) (PMID: 23533021, PMID: 32917322). Multiple homozygous individuals with progressive familial intrahepatic cholestasis (PFIC) have also been reported (PMID: 29761167, Lin H. et al. (2014)). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate in three unrelated families with PFIC (PMID: 29761167, Lin H. et al. (2014)). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Progressive familial intrahepatic cholestasis type 3;C2609268:Low phospholipid associated cholelithiasis;C3554241:Cholestasis, intrahepatic, of pregnancy, 3 Pathogenic:1 Uncertain:1

May 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 06, 2024

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

ABCB4-related disorder Pathogenic:1

Jun 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCB4 c.2177C>T variant is predicted to result in the amino acid substitution p.Pro726Leu. This variant in the presence and absence of a second causative variant has been reported in patients with progressive familial intrahepatic cholestasis type 3 (PFIC3) or low-phospholipid-associated cholelithiasis (see for example Poupon et al. 2013. PubMed ID: 23533021; Delaunay et al. 2016. PubMed ID: 26474921; Elderman et al. 2015. PubMed ID: 25612754). Functional studies demonstrated that this variant resulted in near absence of phosphatidylcholine secretion (Delaunay et al. 2016. PubMed ID: 26474921). Additionally, a different substitution of the same amino acid (p.Pro726Thr) has been well documented as causative for PFIC3 (Degiorgio et al. 2007. PubMed ID: 17726488). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. In ClinVar, this variant is interpreted as likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/194709/). This variant is interpreted as likely pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0	.;.;D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.0	.;T;T;T;.
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;H
PhyloP100		9.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.0	.;D;D;D;D
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D
Vest4		0.0
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.93
gMVP		0.89
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs141677867; hg19: chr7-87053256; COSMIC: COSV99710562; COSMIC: COSV99710562;