ClinVar Genomic variation as it relates to human health
NM_000443.4(ABCB4):c.959C>T (p.Ser320Phe)
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.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000443.4(ABCB4):c.959C>T (p.Ser320Phe)
Variation ID: 13690 Accession: VCV000013690.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q21.12 7: 87447080 (GRCh38) [ NCBI UCSC ] 7: 87076396 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 4, 2013 Aug 4, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000443.4:c.959C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000434.1:p.Ser320Phe missense NM_018849.3:c.959C>T NP_061337.1:p.Ser320Phe missense NM_018850.3:c.959C>T NP_061338.1:p.Ser320Phe missense NC_000007.14:g.87447080G>A NC_000007.13:g.87076396G>A NG_007118.2:g.38353C>T P21439:p.Ser320Phe - Protein change
- S320F
- Other names
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- Canonical SPDI
- NC_000007.14:87447079:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00012
Trans-Omics for Precision Medicine (TOPMed) 0.00015
The Genome Aggregation Database (gnomAD), exomes 0.00016
The Genome Aggregation Database (gnomAD) 0.00018
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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. |
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ABCB4 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
906 | 965 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 4, 2022 | RCV000014688.30 | |
Pathogenic (2) |
no assertion criteria provided
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Oct 1, 2009 | RCV000033065.28 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Jul 24, 2023 | RCV000190560.7 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2024 | RCV000498517.27 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 2, 2023 | RCV003226159.2 | |
ABCB4-related disorder
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Likely pathogenic (1) |
criteria provided, single submitter
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Nov 28, 2023 | RCV004532350.1 |
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. |
More information
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. |
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Pathogenic
(Aug 24, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000706335.2
First in ClinVar: Sep 14, 2015 Last updated: Aug 20, 2017 |
Number of individuals with the variant: 9
Sex: mixed
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Pathogenic
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Cholecystitis
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000470156.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
Across a selection of the available literature, the ABCB4 c.959C>T (p.Ser320Phe) missense variant has been identified in a homozygous state in four patients with intrahepatic … (more)
Across a selection of the available literature, the ABCB4 c.959C>T (p.Ser320Phe) missense variant has been identified in a homozygous state in four patients with intrahepatic cholestasis of pregnancy, in a homozygous state in one patient with progressive familial intrahepatic cholestasis type 3, in a homozygous state in one patient with low phospholipid associated cholelithiasis, and in a compound heterozygotes state in seven patients with progressive familial intrahepatic cholestasis type 3 (Rosmorduc et al. 2001; Rosmorduc et al. 2003; Pauli-Magnus et al. 2004; Keitel et al. 2006; Degiorgio et al. 2007; Colombo et al. 2011; Oliveira et al. 2016). The p.Ser320Phe variant was absent from 630 controls and is reported at a frequency of 0.00020 in the European (non-Finnish) population of the Exome Aggregation Consortium. Transfection of the p.Ser320Phe variant into HEK293T and MDCK-II cells showed that the variant protein had similar activity as compared to wild type, however the expression levels were slightly reduced (Kim et al. 2013; Andress et al. 2014; Gordo-Gilart et al. 2016). Based on the evidence, the p.Ser320Phe variant is classified as pathogenic for ABCB4-related intrahepatic cholestasis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Low phospholipid associated cholelithiasis
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002517498.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Mar 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Progressive familial intrahepatic cholestasis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922668.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: ABCB4 c.959C>T (p.Ser320Phe) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded … (more)
Variant summary: ABCB4 c.959C>T (p.Ser320Phe) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 0.00016 in 251176 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis (0.00016 vs 0.0022), allowing no conclusion about variant significance. c.959C>T has been reported in the literature in multiple individuals affected with Familial Intrahepatic Cholestasis (example: Rosmmorduc_2001 and de Vries_2020). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000589676.4
First in ClinVar: Aug 20, 2017 Last updated: May 20, 2023 |
Comment:
One in vitro study showed decreased transport activity, while another showed reduced protein expression but normal protein function (Kim et al., 2013; Gordo-Gilart et al., … (more)
One in vitro study showed decreased transport activity, while another showed reduced protein expression but normal protein function (Kim et al., 2013; Gordo-Gilart et al., 2016); 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: 19490418, 17562004, 26699824, 32893960, 32650689, 33258288, 33390354, 23533021, 24381502, 22331132, 11313316, 19840255, 17786139, 19584064, 15077010, 16890614, 17726488, 21119540, 26324191, 28776642, 29761167, 24806754, 28733223, 30487145, 31538484, 32793533, 32581362, 26153658, 34376370) (less)
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Pathogenic
(Jul 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001962061.18
First in ClinVar: Oct 07, 2021 Last updated: Aug 04, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003457569.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 320 of the ABCB4 protein (p.Ser320Phe). … (more)
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 320 of the ABCB4 protein (p.Ser320Phe). This variant is present in population databases (rs72552778, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of autosomal recessive progressive familial intrahepatic cholestasis type 3 (PMID: 11313316, 32893960). ClinVar contains an entry for this variant (Variation ID: 13690). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCB4 protein function. Studies have shown that this missense change alters ABCB4 gene expression (PMID: 24806754). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Nov 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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ABCB4-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004115331.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
The ABCB4 c.959C>T variant is predicted to result in the amino acid substitution p.Ser320Phe. This variant has been reported in the homozygous or compound heterozygous … (more)
The ABCB4 c.959C>T variant is predicted to result in the amino acid substitution p.Ser320Phe. This variant has been reported in the homozygous or compound heterozygous state in several individuals with cholestasis phenotypes (see for example, Rosmorduc et al. 2001. PubMed ID: 11313316; Keitel et al. 2006. PubMed ID: 16890614; Degiorgio et al. 2007 PubMed ID: 17726488). In vitro functional assessment has been inconclusive (Kim et al. 2013. PubMed ID: 24381502; Andress et al. 2014. PubMed ID: 24806754; Gordo-Gilart et al. 2015. PubMed ID: 26153658). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. (less)
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Pathogenic
(Oct 01, 2009)
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no assertion criteria provided
Method: literature only
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CHOLESTASIS, INTRAHEPATIC, OF PREGNANCY, 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000056845.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a woman with gallbladder disease-1 (GBD1; 600803) presenting as chronic low phospholipid-associated cholelithiasis (LPAC), which worsened during pregnancy, Rosmorduc et al. (2001) identified a … (more)
In a woman with gallbladder disease-1 (GBD1; 600803) presenting as chronic low phospholipid-associated cholelithiasis (LPAC), which worsened during pregnancy, Rosmorduc et al. (2001) identified a homozygous 959C-T transition in exon 9 of the ABCB4 gene, resulting in a ser320-to-phe (S320F) substitution. An unrelated woman with oral contraceptive-induced cholelithiasis (OCIC; see 614972) was also found to carry a homozygous S320F substitution. Unaffected family members in both families were heterozygous for the mutation. Bacq et al. (2009) identified a heterozygous S320F mutation in 1 of 50 French women with intrahepatic cholestasis of pregnancy (ICP3; 614972). The mutation was not found in 214 control chromosomes. The S320F mutation occurred in transmembrane domain-5. (less)
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Pathogenic
(Oct 01, 2009)
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no assertion criteria provided
Method: literature only
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GALLBLADDER DISEASE 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034943.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a woman with gallbladder disease-1 (GBD1; 600803) presenting as chronic low phospholipid-associated cholelithiasis (LPAC), which worsened during pregnancy, Rosmorduc et al. (2001) identified a … (more)
In a woman with gallbladder disease-1 (GBD1; 600803) presenting as chronic low phospholipid-associated cholelithiasis (LPAC), which worsened during pregnancy, Rosmorduc et al. (2001) identified a homozygous 959C-T transition in exon 9 of the ABCB4 gene, resulting in a ser320-to-phe (S320F) substitution. An unrelated woman with oral contraceptive-induced cholelithiasis (OCIC; see 614972) was also found to carry a homozygous S320F substitution. Unaffected family members in both families were heterozygous for the mutation. Bacq et al. (2009) identified a heterozygous S320F mutation in 1 of 50 French women with intrahepatic cholestasis of pregnancy (ICP3; 614972). The mutation was not found in 214 control chromosomes. The S320F mutation occurred in transmembrane domain-5. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Cholestasis, intrahepatic, of pregnancy, 3
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001161919.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Observation 1:
Number of individuals with the variant: 1
Sex: female
Observation 2:
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931835.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001968202.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Uncertain significance
(Aug 22, 2014)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Progressive familial intrahepatic cholestasis 3
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Study: CSER-MedSeq
Accession: SCV000245567.1 First in ClinVar: Sep 14, 2015 Last updated: Sep 14, 2015 |
Comment:
The Ser320Phe variant in ABCB4 has been reported in 9 heterozygous, 6 homozygous, and 4 compound heterozygous individuals with cholestatic liver disease (Andress 2014, Poupon … (more)
The Ser320Phe variant in ABCB4 has been reported in 9 heterozygous, 6 homozygous, and 4 compound heterozygous individuals with cholestatic liver disease (Andress 2014, Poupon 2013, Wendum 2012, Bacq 2009, Degiorgio 2007, Colombo 2011, Rosmorduc 2001, Pauli-Magnus 2004, Zimmer 2009, Keitel 2006). This variant has been identified in 1/8600 of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs72552778). Computational analyses (biochemical amino acid properties, conservation and PolyPhen2) do not provide strong support for or against an impact to the protein. In vitro assays suggest the Ser320Phe variant may affect protein function (Andress 2014, Kim 2013); however these types of assays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the Ser320Phe variant is uncertain. (less)
Number of individuals with the variant: 1
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 |
Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
Elevation of gamma-glutamyl transferase in adult: Should we think about progressive familiar intrahepatic cholestasis? | Oliveira HM | Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver | 2016 | PMID: 26699824 |
Heterozygous ABCB4 mutations in children with cholestatic liver disease. | Gordo-Gilart R | Liver international : official journal of the International Association for the Study of the Liver | 2016 | PMID: 26153658 |
Molecular mechanistic explanation for the spectrum of cholestatic disease caused by the S320F variant of ABCB4. | Andress EJ | Hepatology (Baltimore, Md.) | 2014 | PMID: 24806754 |
Functional Characterization of ABCB4 Mutations Found in Low Phospholipid-Associated Cholelithiasis (LPAC). | Kim TH | The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology | 2013 | PMID: 24381502 |
Genotype-phenotype relationships in the low-phospholipid-associated cholelithiasis syndrome: a study of 156 consecutive patients. | Poupon R | Hepatology (Baltimore, Md.) | 2013 | PMID: 23533021 |
Aspects of liver pathology in adult patients with MDR3/ABCB4 gene mutations. | Wendum D | Virchows Archiv : an international journal of pathology | 2012 | PMID: 22331132 |
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 |
Combined features of low phospholipid-associated cholelithiasis and progressive familial intrahepatic cholestasis 3. | Poupon R | Liver international : official journal of the International Association for the Study of the Liver | 2010 | PMID: 19840255 |
ABCB4 gene mutations and single-nucleotide polymorphisms in women with intrahepatic cholestasis of pregnancy. | Bacq Y | Journal of medical genetics | 2009 | PMID: 19584064 |
Combined functional variants of hepatobiliary transporters and FXR aggravate intrahepatic cholestasis of pregnancy. | Zimmer V | Liver international : official journal of the International Association for the Study of the Liver | 2009 | PMID: 19490418 |
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 |
Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy. | Keitel V | Gastroenterology | 2006 | PMID: 16890614 |
Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy. | Pauli-Magnus C | Pharmacogenetics | 2004 | PMID: 15077010 |
ABCB4 gene mutation-associated cholelithiasis in adults. | Rosmorduc O | Gastroenterology | 2003 | PMID: 12891548 |
MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis. | Rosmorduc O | Gastroenterology | 2001 | PMID: 11313316 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCB4 | - | - | - | - |
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Text-mined citations for rs72552778 ...
HelpRecord last updated Sep 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.