The ABCC2 c.3517A>T (p.Ile1173Phe) missense variant has been reported in a single study in which it was found in a total of 24 individuals with Dubin-Johnson syndrome, including in a homozygous state in 22 patients of Iranian Jewish origin and in a compound heterozygous state in two patients of mixed Iranian Jewish and Moroccan Jewish origin (Mor-Cohen et al. 2001). The p.Ile1173Phe variant was also detected in a heterozygous state in 14 of 243 healthy Iranian Jewish controls and is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. Expression studies indicated that the p.Ile1173Phe variant resulted in impaired transport activity of the ABCC2 protein, expression of the variant protein was low, and the variant protein itself mislocated to the endoplasmic reticulum (Mor-Cohen et al. 2001). Based on the collective evidence, the p.Ile1173Phe variant is classified as pathogenic for Dubin-Johnson syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ClinVar Genomic variation as it relates to human health
NM_000392.5(ABCC2):c.3517A>T (p.Ile1173Phe)
Germline
Classification
Help
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.
(6)
Help
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.
Pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000392.5(ABCC2):c.3517A>T (p.Ile1173Phe)
Variation ID: 8418 Accession: VCV000008418.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q24.2 10: 99836193 (GRCh38) [ NCBI UCSC ] 10: 101595950 (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 Sep 18, 2016 Feb 14, 2024 Jan 31, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000392.5:c.3517A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000383.2:p.Ile1173Phe missense NC_000010.11:g.99836193A>T NC_000010.10:g.101595950A>T NG_011798.2:g.58596A>T LRG_1208:g.58596A>T LRG_1208t1:c.3517A>T LRG_1208p1:p.Ile1173Phe Q92887:p.Ile1173Phe - Protein change
- I1173F
- Other names
- -
- Canonical SPDI
- NC_000010.11:99836192:A:T
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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.
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The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| ABCC2 | - | - |
GRCh38 GRCh37 |
980 | 1150 | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 6, 2019 | RCV000008929.11 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2024 | RCV000727693.7 |
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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|---|---|---|---|---|---|
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Pathogenic
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Dubin-Johnson syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000359803.3
First in ClinVar: Dec 06, 2016 Last updated: May 27, 2019 |
Comment:
The ABCC2 c.3517A>T (p.Ile1173Phe) missense variant has been reported in a single study in which it was found in a total of 24 individuals with … (more)
The ABCC2 c.3517A>T (p.Ile1173Phe) missense variant has been reported in a single study in which it was found in a total of 24 individuals with Dubin-Johnson syndrome, including in a homozygous state in 22 patients of Iranian Jewish origin and in a compound heterozygous state in two patients of mixed Iranian Jewish and Moroccan Jewish origin (Mor-Cohen et al. 2001). The p.Ile1173Phe variant was also detected in a heterozygous state in 14 of 243 healthy Iranian Jewish controls and is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. Expression studies indicated that the p.Ile1173Phe variant resulted in impaired transport activity of the ABCC2 protein, expression of the variant protein was low, and the variant protein itself mislocated to the endoplasmic reticulum (Mor-Cohen et al. 2001). Based on the collective evidence, the p.Ile1173Phe variant is classified as pathogenic for Dubin-Johnson syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
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Pathogenic
(Mar 27, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000855036.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
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Pathogenic
(Sep 06, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Dubin-Johnson syndrome
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001521393.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
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Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003263529.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1173 of the ABCC2 protein (p.Ile1173Phe). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1173 of the ABCC2 protein (p.Ile1173Phe). This variant is present in population databases (rs72558201, gnomAD 0.004%). This missense change has been observed in individuals with Dubin-Johnson syndrome (PMID: 11477083, 31544333). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8418). 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 ABCC2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ABCC2 function (PMID: 11477083, 12388192, 22290738). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 05, 2001)
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no assertion criteria provided
Method: literature only
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DUBIN-JOHNSON SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029139.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 18, 2016 |
Comment on evidence:
In 22 Iranian Jewish patients with Dubin-Johnson syndrome (DJS; 237500) from 13 unrelated families, Mor-Cohen et al. (2001) screened all 32 exons and adjacent regions … (more)
In 22 Iranian Jewish patients with Dubin-Johnson syndrome (DJS; 237500) from 13 unrelated families, Mor-Cohen et al. (2001) screened all 32 exons and adjacent regions of the MRP2 gene and identified homozygosity for a 3517A-T transversion in exon 25, predicting an ile1173-to-phe (I1173F) substitution. Use of 4 intragenic dimorphisms and haplotype analyses disclosed a specific founder effect. The mutation was introduced into an MRP2 expression vector by site-directed mutagenesis, transfected into HEK293 cells, and analyzed by a fluorescence transport assay, immunoblot, and immunocytochemistry. The studies demonstrated that the mutation impaired the transport activity of MRP2. Immunoblot analysis and immunocytochemistry showed that expression of the mutation was low and mislocated to the endoplasmic reticulum of the transfected cells. (less)
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Dubin-Johnson syndrome
Affected status: unknown
Allele origin:
germline
|
FirmaLab, FirmaLab
Accession: SCV000106041.1
First in ClinVar: Mar 16, 2017 Last updated: Mar 16, 2017 |
|
Comment:
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1173 of the ABCC2 protein (p.Ile1173Phe). This variant is present in population databases (rs72558201, gnomAD 0.004%). This missense change has been observed in individuals with Dubin-Johnson syndrome (PMID: 11477083, 31544333). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8418). 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 ABCC2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ABCC2 function (PMID: 11477083, 12388192, 22290738). For these reasons, this variant has been classified as Pathogenic.
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. |
Comment:
The ABCC2 c.3517A>T (p.Ile1173Phe) missense variant has been reported in a single study in which it was found in a total of 24 individuals with Dubin-Johnson syndrome, including in a homozygous state in 22 patients of Iranian Jewish origin and in a compound heterozygous state in two patients of mixed Iranian Jewish and Moroccan Jewish origin (Mor-Cohen et al. 2001). The p.Ile1173Phe variant was also detected in a heterozygous state in 14 of 243 healthy Iranian Jewish controls and is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. Expression studies indicated that the p.Ile1173Phe variant resulted in impaired transport activity of the ABCC2 protein, expression of the variant protein was low, and the variant protein itself mislocated to the endoplasmic reticulum (Mor-Cohen et al. 2001). Based on the collective evidence, the p.Ile1173Phe variant is classified as pathogenic for Dubin-Johnson syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1173 of the ABCC2 protein (p.Ile1173Phe). This variant is present in population databases (rs72558201, gnomAD 0.004%). This missense change has been observed in individuals with Dubin-Johnson syndrome (PMID: 11477083, 31544333). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8418). 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 ABCC2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ABCC2 function (PMID: 11477083, 12388192, 22290738). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic contribution of ABCC2 to Dubin-Johnson syndrome and inherited cholestatic disorders. | Corpechot C | Liver international : official journal of the International Association for the Study of the Liver | 2020 | PMID: 31544333 |
| Functional characterization of protein variants of the human multidrug transporter ABCC2 by a novel targeted expression system in fibrosarcoma cells. | Arlanov R | Human mutation | 2012 | PMID: 22290738 |
| A common Dubin-Johnson syndrome mutation impairs protein maturation and transport activity of MRP2 (ABCC2). | Keitel V | American journal of physiology. Gastrointestinal and liver physiology | 2003 | PMID: 12388192 |
| Identification and functional analysis of two novel mutations in the multidrug resistance protein 2 gene in Israeli patients with Dubin-Johnson syndrome. | Mor-Cohen R | The Journal of biological chemistry | 2001 | PMID: 11477083 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCC2 | - | - | - | - |
Text-mined citations for rs72558201 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.