ClinVar Genomic variation as it relates to human health
NM_000443.4(ABCB4):c.1529A>G (p.Asn510Ser)
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.
Pathogenic(5); Likely pathogenic(4); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000443.4(ABCB4):c.1529A>G (p.Asn510Ser)
Variation ID: 291252 Accession: VCV000291252.46
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q21.12 7: 87440230 (GRCh38) [ NCBI UCSC ] 7: 87069546 (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 Mar 8, 2017 Oct 8, 2024 Aug 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000443.4:c.1529A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000434.1:p.Asn510Ser missense NM_018849.3:c.1529A>G NP_061337.1:p.Asn510Ser missense NM_018850.3:c.1529A>G NP_061338.1:p.Asn510Ser missense NC_000007.14:g.87440230T>C NC_000007.13:g.87069546T>C NG_007118.2:g.45203A>G P21439:p.Asn510Ser - Protein change
- N510S
- Other names
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- Canonical SPDI
- NC_000007.14:87440229: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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0.00020 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00009
1000 Genomes Project 30x 0.00016
Exome Aggregation Consortium (ExAC) 0.00018
Trans-Omics for Precision Medicine (TOPMed) 0.00019
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00020
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 | ||
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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
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. |
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ABCB4 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
932 | 991 |
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. |
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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2024 | RCV000427203.36 | |
Pathogenic (2) |
criteria provided, single submitter
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Aug 12, 2023 | RCV001003941.5 | |
Pathogenic (1) |
criteria provided, single submitter
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May 28, 2019 | RCV000987913.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 14, 2023 | RCV002298568.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 12, 2023 | RCV003333058.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 25, 2024 | RCV003989523.2 | |
ABCB4-related disorder
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Likely pathogenic (1) |
no assertion criteria provided
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Aug 28, 2024 | RCV004537625.3 |
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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Likely pathogenic
(Jul 17, 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: SCV000345967.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 4
Sex: mixed
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Progressive familial intrahepatic cholestasis type 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001137406.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Aug 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cholestasis, intrahepatic, of pregnancy, 3
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001521454.2
First in ClinVar: Mar 22, 2021 Last updated: Oct 06, 2023 |
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Pathogenic
(Aug 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Progressive familial intrahepatic cholestasis type 3
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004041259.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Pathogenic
(Feb 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Progressive familial intrahepatic cholestasis type 3
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004176544.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Clinical Features:
Abnormality of the liver (present)
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Likely pathogenic
(Apr 08, 2022)
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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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Revvity Omics, Revvity
Accession: SCV002021001.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Dec 14, 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: SCV002598623.2
First in ClinVar: Nov 05, 2022 Last updated: Feb 04, 2024 |
Comment:
Variant summary: ABCB4 c.1529A>G (p.Asn510Ser) results in a conservative amino acid change located in the first ATP-binding domain (IPR003439) of the encoded protein sequence. Four … (more)
Variant summary: ABCB4 c.1529A>G (p.Asn510Ser) results in a conservative amino acid change located in the first ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251250 control chromosomes, predominantly at a frequency of 0.00062 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not higher than the estimated maximum expected for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis (0.0022), allowing no conclusion about variant significance. The variant, c.1529A>G, has been reported in the literature in (presumed) compound heterozygous state together with a second (likely) pathogenic variant in individuals affected with hepatobiliary disease and intrahepatic cholestasis of pregnancy (e.g. Delaunay_2016, Stalke_2018, Falcao_2022). The variant has been also reported in (apparent) heterozygosity in affected individuals in whom a second (likely) pathogenic mutation was not identified. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated decreased protein stability (Delaunay_2016). The following publications have been ascertained in the context of this evaluation (PMID: 32917322, 26324191, 26474921, 28587926, 32626542, 28776642, 19467940, 34376370). Eight other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant with conflicting assessments, i.e. as pathogenic (n=3), likely pathogenic (n=4), or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Jan 19, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003263803.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 510 of the ABCB4 protein (p.Asn510Ser). … (more)
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 510 of the ABCB4 protein (p.Asn510Ser). This variant is present in population databases (rs375315619, gnomAD 0.06%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with autosomal recessive progressive familial intrahepatic cholestasis type 3 and/or intrahepatic cholestasis of pregnancy (PMID: 23022423, 23533021, 26324191, 26474921, 28776642, 32581362, 32917322, 34376370). ClinVar contains an entry for this variant (Variation ID: 291252). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Studies have shown that this missense change alters ABCB4 gene expression (PMID: 26474921). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Uncertain significance
(Mar 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Severe early-childhood-onset retinal dystrophy
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806278.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Aug 01, 2024)
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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: SCV001155111.26
First in ClinVar: Feb 03, 2020 Last updated: Oct 08, 2024 |
Comment:
ABCB4: PM3:Very Strong, PM2, PP4, PS3:Supporting
Number of individuals with the variant: 8
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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: SCV001161915.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Number of individuals with the variant: 1
Sex: female
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Likely pathogenic
(Aug 28, 2024)
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no assertion criteria provided
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: SCV004116808.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The ABCB4 c.1529A>G variant is predicted to result in the amino acid substitution p.Asn510Ser. In the heterozygous state alone, this variant was reported in patients … (more)
The ABCB4 c.1529A>G variant is predicted to result in the amino acid substitution p.Asn510Ser. In the heterozygous state alone, this variant was reported in patients with intrahepatic cholestasis of pregnancy (ICP) (Anzivino. 2013. PubMed ID: 23022423; Poupon. 2013. PubMed ID: 23533021; Falcão. 2021. PubMed ID: 34376370; Stalke 2017. PubMed ID: 28776642). In the compound heterozygous state with another pathogenic ABCB4 variant, this variant was reported to cause progressive familial intrahepatic cholestasis (PFIC) (Delaunay. 2015. PubMed ID: 26474921; Davit-Spraul. 2010. PubMed ID: 20422496; Falcão. 2021. PubMed ID: 34376370). Functional assays in the Delaunay study indicated the p.Asn510Ser change reduced protein stability. This variant is reported in 0.062% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic. (less)
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Uncertain Significance
(Oct 25, 2016)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000510673.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Converted during submission to Uncertain significance.
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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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The wide phenotypic and genetic spectrum of ABCB4 gene deficiency: A case series. | Falcão D | Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver | 2022 | PMID: 34376370 |
The role of genetic mutations in intrahepatic cholestasis of pregnancy. | Aydın GA | Taiwanese journal of obstetrics & gynecology | 2020 | PMID: 32917322 |
Evaluation of a Novel Missense Mutation in ABCB4 Gene Causing Progressive Familial Intrahepatic Cholestasis Type 3. | Saleem K | Disease markers | 2020 | PMID: 32626542 |
Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
Diagnosis of monogenic liver diseases in childhood by next-generation sequencing. | Stalke A | Clinical genetics | 2018 | PMID: 28776642 |
Comparison of in silico prediction and experimental assessment of ABCB4 variants identified in patients with biliary diseases. | Khabou B | The international journal of biochemistry & cell biology | 2017 | PMID: 28587926 |
A functional classification of ABCB4 variations causing progressive familial intrahepatic cholestasis type 3. | Delaunay JL | Hepatology (Baltimore, Md.) | 2016 | PMID: 26474921 |
ABCB4 mutations in adult patients with cholestatic liver disease: impact and phenotypic expression. | Degiorgio D | Journal of gastroenterology | 2016 | PMID: 26324191 |
Genotype-phenotype relationships in the low-phospholipid-associated cholelithiasis syndrome: a study of 156 consecutive patients. | Poupon R | Hepatology (Baltimore, Md.) | 2013 | PMID: 23533021 |
ABCB4 and ABCB11 mutations in intrahepatic cholestasis of pregnancy in an Italian population. | Anzivino C | Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver | 2013 | PMID: 23022423 |
An MBL2 haplotype and ABCB4 variants modulate the risk of liver disease in cystic fibrosis patients: a multicentre study. | Tomaiuolo R | Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver | 2009 | PMID: 19467940 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCB4 | - | - | - | - |
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Text-mined citations for rs375315619 ...
HelpRecord last updated Oct 13, 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.