ClinVar Genomic variation as it relates to human health
NM_003742.4(ABCB11):c.2012-8T>G
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_003742.4(ABCB11):c.2012-8T>G
Variation ID: 284637 Accession: VCV000284637.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q31.1 2: 168968498 (GRCh38) [ NCBI UCSC ] 2: 169825008 (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 Dec 6, 2016 Jun 17, 2024 Feb 12, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003742.4:c.2012-8T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000002.12:g.168968498A>C NC_000002.11:g.169825008A>C NG_007374.2:g.67899T>G LRG_1199:g.67899T>G LRG_1199t1:c.2012-8T>G - Protein change
- Other names
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- Canonical SPDI
- NC_000002.12:168968497:A:C
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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
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00006
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
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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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ABCB11 | - | - |
GRCh38 GRCh38 GRCh37 |
1497 | 1600 |
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
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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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Dec 21, 2023 | RCV000339283.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763464.3 | |
Likely pathogenic (1) |
no assertion criteria provided
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- | RCV001003555.2 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Oct 23, 2018 | RCV000779283.7 | |
ABCB11-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Aug 4, 2023 | RCV003401248.4 |
Pathogenic (1) |
criteria provided, single submitter
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Feb 12, 2024 | RCV003463756.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 11, 2023 | RCV003492026.1 |
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
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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
(Feb 01, 2017)
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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: SCV000337332.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 8
Sex: mixed
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Progressive familial intrahepatic cholestasis type 2
Benign recurrent intrahepatic cholestasis type 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894241.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Likely pathogenic
(Oct 23, 2018)
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criteria provided, single submitter
Method: clinical testing
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Progressive familial intrahepatic cholestasis type 2
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915865.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The ABCB11 c.2012-8T>G variant has been identified in a compound heterozygous state in at least six probands and in a heterozygous state in one proband … (more)
The ABCB11 c.2012-8T>G variant has been identified in a compound heterozygous state in at least six probands and in a heterozygous state in one proband in whom a second variant was not identified, all with familial intrahepatic cholestasis (Knisely et al. 2006; Siebold et al. 2010; Strautnieks et al. 2008; Grammatikopoulos et al. 2015). The c.2012-8T>G variant was absent from 500 control individuals and is reported at a frequency of 0.000056 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the c.2012-8T>G variant is classified as likely pathogenic for familial 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
(Mar 13, 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: SCV004035430.1
First in ClinVar: Sep 23, 2023 Last updated: Sep 23, 2023 |
Comment:
Non-canonical splice site variant demonstrated to result in loss of function (Strautnieks et al., 2008); This variant is associated with the following publications: (PMID: 16871584, … (more)
Non-canonical splice site variant demonstrated to result in loss of function (Strautnieks et al., 2008); This variant is associated with the following publications: (PMID: 16871584, 32581362, 35894240, 24402531, 20583290, 24231640, 18395098) (less)
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Pathogenic
(Aug 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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ABCB11-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004105719.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The ABCB11 c.2012-8T>G variant is predicted to interfere with splicing. This variant was previously reported in the compound heterozygous state in individuals who presented with … (more)
The ABCB11 c.2012-8T>G variant is predicted to interfere with splicing. This variant was previously reported in the compound heterozygous state in individuals who presented with familial intrahepatic cholestasis (Knisely et al. 2006. PubMed ID: 16871584, reported as IVS16-8T>G; Siebold et al. 2010. PubMed ID: 20583290; Strautnieks et al. 2008. PubMed ID: 18395098). In vitro analysis from one study indicated that this variant led to skipping of exon 17 and a resulting frameshift with premature protein termination (Knisely et al. 2006. PubMed ID: 16871584). This variant is reported in 0.0056% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-169825008-A-C) and is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/284637/). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Dec 11, 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: SCV004240833.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: ABCB11 c.2012-8T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: ABCB11 c.2012-8T>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 3' cryptic acceptor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.5e-05 in 244560 control chromosomes. c.2012-8T>G has been reported in the literature at a compound heterozygous state along with difference pathogenic variants in multiple individuals affected with Familial Intrahepatic Cholestasis (examples, Knisely_2006, Strautnieks_2008). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on splicing, however, detailed information of such results are not available for an independent evaluation (Strautnieks_2008). The following publications have been ascertained in the context of this evaluation (PMID: 16871584, 18395098). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 21, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000956198.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 16 of the ABCB11 gene. It does not directly change the encoded amino acid sequence of the ABCB11 protein. … (more)
This sequence change falls in intron 16 of the ABCB11 gene. It does not directly change the encoded amino acid sequence of the ABCB11 protein. This variant is present in population databases (rs769910565, gnomAD 0.006%). This variant has been observed in individuals with ABCB11-related conditions (PMID: 18395098). ClinVar contains an entry for this variant (Variation ID: 284637). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 12, 2024)
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criteria provided, single submitter
Method: clinical testing
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Benign recurrent intrahepatic cholestasis type 2
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004198059.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Likely 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: SCV001161899.1
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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Likely pathogenic
(Jan 22, 2021)
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no assertion criteria provided
Method: clinical testing
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Progressive familial intrahepatic cholestasis type 2
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002077899.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
Anti-CD20 Monoclonal Antibody Therapy in Functional Bile Salt Export Pump Deficiency After Liver Transplantation. | Grammatikopoulos T | Journal of pediatric gastroenterology and nutrition | 2015 | PMID: 24231640 |
The etiology of intrahepatic cholestasis of pregnancy: towards solving a monkey puzzle. | Webb GJ | The American journal of gastroenterology | 2014 | PMID: 24402531 |
Recurrent low gamma-glutamyl transpeptidase cholestasis following liver transplantation for bile salt export pump (BSEP) disease (posttransplant recurrent BSEP disease). | Siebold L | Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society | 2010 | PMID: 20583290 |
Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. | Strautnieks SS | Gastroenterology | 2008 | PMID: 18395098 |
Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. | Knisely AS | Hepatology (Baltimore, Md.) | 2006 | PMID: 16871584 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCB11 | - | - | - | - |
Text-mined citations for rs769910565 ...
HelpRecord 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.