ClinVar Genomic variation as it relates to human health
NM_001374385.1(ATP8B1):c.923G>T (p.Gly308Val)
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_001374385.1(ATP8B1):c.923G>T (p.Gly308Val)
Variation ID: 7262 Accession: VCV000007262.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.31 18: 57695188 (GRCh38) [ NCBI UCSC ] 18: 55362420 (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 24, 2015 Feb 14, 2024 Sep 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001374385.1:c.923G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001361314.1:p.Gly308Val missense NM_001374386.1:c.773G>T NP_001361315.1:p.Gly258Val missense NM_005603.6:c.923G>T NP_005594.2:p.Gly308Val missense NC_000018.10:g.57695188C>A NC_000018.9:g.55362420C>A NG_007148.3:g.113635G>T LRG_1205:g.113635G>T LRG_1205t1:c.923G>T LRG_1205p1:p.Gly308Val O43520:p.Gly308Val NP_005594.1:p.Gly308Val - Protein change
- G308V, G258V
- Other names
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- Canonical SPDI
- NC_000018.10:57695187:C: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.
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00007
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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ATP8B1 | - | - |
GRCh38 GRCh37 |
512 | 1083 |
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/Likely pathogenic (3) |
no assertion criteria provided
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Sep 26, 2019 | RCV000007684.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 10, 2023 | RCV000730982.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 8, 2023 | RCV003390655.4 |
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
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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
(Jul 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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ATP8B1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004120088.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The ATP8B1 c.923G>T variant is predicted to result in the amino acid substitution p.Gly308Val. This variant was reported in the homozygous or compound heterozygous state … (more)
The ATP8B1 c.923G>T variant is predicted to result in the amino acid substitution p.Gly308Val. This variant was reported in the homozygous or compound heterozygous state to be causative for intrahepatic cholestasis (Bull et al. 1998. PubMed ID: 9500542; Table S2, Hertel et al. 2021. PubMed ID: 34016879). Functional studies using cell cultures and mouse models also support the pathogenicity (Pawlikowska et al. 2004. PubMed ID: 14976163; Folmer et al. 2009. PubMed ID: 19731236; van der Velden et al. 2010. PubMed ID: 19918981). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-55362420-C-A). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Sep 10, 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: SCV004331226.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 308 of the ATP8B1 protein (p.Gly308Val). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 308 of the ATP8B1 protein (p.Gly308Val). This variant is present in population databases (rs111033609, gnomAD 0.007%). This missense change has been observed in individuals with progressive familial intrahepatic cholestasis type 1 (PMID: 9500542, 33666275, 34016879). ClinVar contains an entry for this variant (Variation ID: 7262). 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 ATP8B1 protein function. Experimental studies have shown that this missense change affects ATP8B1 function (PMID: 14976163, 19381753, 19918981). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 19, 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: SCV000858752.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Oct 01, 2010)
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no assertion criteria provided
Method: literature only
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CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027885.3
First in ClinVar: Apr 04, 2013 Last updated: May 20, 2016 |
Comment on evidence:
In affected members of the Amish kindred in which Byler disease, or progressive familial intrahepatic cholestasis (PFIC1; 211600), was first described by Clayton et al. … (more)
In affected members of the Amish kindred in which Byler disease, or progressive familial intrahepatic cholestasis (PFIC1; 211600), was first described by Clayton et al. (1969), Bull et al. (1998) demonstrated a homozygous 923G-T transversion in the ATP8B1 gene, resulting in a gly308-to-val (G308V) substitution. Ray et al. (2010) noted that patients with PFIC1 and mice expressing mutant Atp8b1 are prone to bacterial pneumonia. They found that bronchial lavage fluid of mice with the G308V mutation in Atp8b1 had elevated cardiolipin levels and showed a blunted response to T-helper type-1 cytokines. Primary mutant type II lung cells exhibited reduced ability to uptake cardiolipin and were prone to apoptosis. (less)
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Likely pathogenic
(Sep 26, 2019)
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no assertion criteria provided
Method: clinical testing
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Progressive familial intrahepatic cholestasis type 1
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001133180.1
First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020 |
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not provided
(-)
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no classification provided
Method: literature only
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Progressive familial intrahepatic cholestasis type 1
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000147887.4
First in ClinVar: Apr 19, 2014 Last updated: Oct 01, 2022 |
Comment:
Founder variant in Amish population
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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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Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children With Monogenic Cholestasis. | Hertel PM | Journal of pediatric gastroenterology and nutrition | 2021 | PMID: 34016879 |
Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency. | van Wessel DBE | Hepatology (Baltimore, Md.) | 2021 | PMID: 33666275 |
ATP8B1 Deficiency. | Adam MP | - | 2021 | PMID: 20301474 |
Clinical Variability After Partial External Biliary Diversion in Familial Intrahepatic Cholestasis 1 Deficiency. | Squires JE | Journal of pediatric gastroenterology and nutrition | 2017 | PMID: 28045770 |
Possible Phenylacetate Hepatotoxicity During 4-Phenylbutyrate Therapy of Byler Disease. | Shneider BL | Journal of pediatric gastroenterology and nutrition | 2016 | PMID: 26756876 |
Dynamic regulation of cardiolipin by the lipid pump Atp8b1 determines the severity of lung injury in experimental pneumonia. | Ray NB | Nature medicine | 2010 | PMID: 20852622 |
Folding defects in P-type ATP 8B1 associated with hereditary cholestasis are ameliorated by 4-phenylbutyrate. | van der Velden LM | Hepatology (Baltimore, Md.) | 2010 | PMID: 19918981 |
Differential effects of progressive familial intrahepatic cholestasis type 1 and benign recurrent intrahepatic cholestasis type 1 mutations on canalicular localization of ATP8B1. | Folmer DE | Hepatology (Baltimore, Md.) | 2009 | PMID: 19731236 |
FIC1-mediated stimulation of FXR activity is decreased with PFIC1 mutations in HepG2 cells. | Koh S | Journal of gastroenterology | 2009 | PMID: 19381753 |
Bile composition in Alagille Syndrome and PFIC patients having Partial External Biliary Diversion. | Emerick KM | BMC gastroenterology | 2008 | PMID: 18937870 |
A mouse genetic model for familial cholestasis caused by ATP8B1 mutations reveals perturbed bile salt homeostasis but no impairment in bile secretion. | Pawlikowska L | Human molecular genetics | 2004 | PMID: 14976163 |
A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. | Bull LN | Nature genetics | 1998 | PMID: 9500542 |
Byler disease. Fatal familial intrahepatic cholestasis in an Amish kindred. | Clayton RJ | American journal of diseases of children (1960) | 1969 | PMID: 5762004 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATP8B1 | - | - | - | - |
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Text-mined citations for rs111033609 ...
HelpRecord last updated Mar 11, 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.