ClinVar Genomic variation as it relates to human health
NM_003742.4(ABCB11):c.1445A>G (p.Asp482Gly)
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.1445A>G (p.Asp482Gly)
Variation ID: 288555 Accession: VCV000288555.43
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q31.1 2: 168972040 (GRCh38) [ NCBI UCSC ] 2: 169828550 (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 May 12, 2024 Oct 5, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003742.4:c.1445A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003733.2:p.Asp482Gly missense NC_000002.12:g.168972040T>C NC_000002.11:g.169828550T>C NG_007374.2:g.64357A>G LRG_1199:g.64357A>G LRG_1199t1:c.1445A>G LRG_1199p1:p.Asp482Gly O95342:p.Asp482Gly - Protein change
- D482G
- Other names
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- Canonical SPDI
- NC_000002.12:168972039:T: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
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
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. |
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ABCB11 | - | - |
GRCh38 GRCh38 GRCh37 |
1451 | 1551 |
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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Oct 5, 2023 | RCV000352712.28 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2022 | RCV000779284.7 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 4, 2023 | RCV001198579.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 5, 2022 | RCV002494878.2 |
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 16, 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: SCV000342702.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Sep 21, 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: SCV000915866.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
Across a selection of the available literature, the ABCB11 c.1445A>G (p.Asp482Gly) variant has been identified in a homozygous state in 11 probands, in a compound … (more)
Across a selection of the available literature, the ABCB11 c.1445A>G (p.Asp482Gly) variant has been identified in a homozygous state in 11 probands, in a compound heterozygous state in 18 probands, and in a heterozygous state in three probands (Strautnieks et al. 1998; Strautnieks et al. 2008; Giovannoni et al. 2015; Varma et al. 2016). The p.Asp482Gly variant was absent from 300 control chromosomes and is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. Strautnieks et al. (2008) showed that there was variability in the level of ABCB11 protein expression that did not correlate with genotype from normal to undetectable. Byrne et al. (2009) demonstrated that the p.Asp482Gly variant caused aberrant splicing with only 5% of normal splicing detected. The variant results in the introduction of 14 amino acids followed by a termination codon. Functional studies have shown that the variant protein is transcribed at comparable levels to the wild type protein and similarly located at the cell surface. However, the total protein expression level is significantly reduced to 2.5% and cell-surface protein expression to 5% of wild type suggesting that the variant reduces protein expression but does not impair trafficking to the membrane. Variant protein has been shown to be only partially glycosylated suggesting less stability. ATPase activity and bile acid transport of the p.Asp482Gly protein were shown to be comparable to wild type (Plass et al. 2004; Hayashi et al. 2005; Lam et al. 2007). Based on the collective evidence, the p.Asp482Gly variant is classified as 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
(Sep 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Benign recurrent intrahepatic cholestasis type 2
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369569.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3,BP1.
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Pathogenic
(Apr 05, 2022)
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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: SCV002786254.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 05, 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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Invitae
Accession: SCV000949907.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 482 of the ABCB11 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 482 of the ABCB11 protein (p.Asp482Gly). This variant is present in population databases (rs72549402, gnomAD 0.004%). This missense change has been observed in individuals with ABCB11-related conditions (PMID: 9806540, 18395098, 26019043). ClinVar contains an entry for this variant (Variation ID: 288555). 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 ABCB11 protein function. Experimental studies have shown that this missense change affects ABCB11 function (PMID: 12370274, 14672610, 19101985). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 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: SCV001246018.19
First in ClinVar: May 09, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 3
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Pathogenic
(Dec 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Progressive familial intrahepatic cholestasis type 2
Affected status: yes
Allele origin:
biparental
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Eurofins-Biomnis
Accession: SCV003935038.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
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Pathogenic
(Oct 04, 2023)
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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: SCV004207085.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 16, 2020)
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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: SCV001459648.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Genetics and Molecular Modeling of New Mutations of Familial Intrahepatic Cholestasis in a Single Italian Center. | Giovannoni I | PloS one | 2015 | PMID: 26678486 |
Successful pregnancy after ileal exclusion in progressive familial intrahepatic cholestasis type 2. | Czubkowski P | Annals of hepatology | 2015 | PMID: 26019043 |
Retargeting of bile salt export pump and favorable outcome in children with progressive familial intrahepatic cholestasis type 2. | Varma S | Hepatology (Baltimore, Md.) | 2015 | PMID: 25847299 |
Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing. | Byrne JA | Hepatology (Baltimore, Md.) | 2009 | PMID: 19101985 |
Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. | Strautnieks SS | Gastroenterology | 2008 | PMID: 18395098 |
Levels of plasma membrane expression in progressive and benign mutations of the bile salt export pump (Bsep/Abcb11) correlate with severity of cholestatic diseases. | Lam P | American journal of physiology. Cell physiology | 2007 | PMID: 17855769 |
Two common PFIC2 mutations are associated with the impaired membrane trafficking of BSEP/ABCB11. | Hayashi H | Hepatology (Baltimore, Md.) | 2005 | PMID: 15791618 |
A progressive familial intrahepatic cholestasis type 2 mutation causes an unstable, temperature-sensitive bile salt export pump. | Plass JR | Journal of hepatology | 2004 | PMID: 14672610 |
The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II. | Wang L | The Journal of clinical investigation | 2002 | PMID: 12370274 |
A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. | Strautnieks SS | Nature genetics | 1998 | PMID: 9806540 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCB11 | - | - | - | - |
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Text-mined citations for rs72549402 ...
HelpRecord last updated May 12, 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.