ClinVar Genomic variation as it relates to human health
NM_001374385.1(ATP8B1):c.208G>A (p.Asp70Asn)
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.
Uncertain significance(7); Benign(2); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001374385.1(ATP8B1):c.208G>A (p.Asp70Asn)
Variation ID: 7271 Accession: VCV000007271.35
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 18q21.31 18: 57706561 (GRCh38) [ NCBI UCSC ] 18: 55373793 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jun 29, 2015 Apr 15, 2024 Mar 25, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001374385.1:c.208G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001361314.1:p.Asp70Asn missense NM_001374386.1:c.130-1893G>A intron variant NM_005603.6:c.208G>A NP_005594.2:p.Asp70Asn missense NC_000018.10:g.57706561C>T NC_000018.9:g.55373793C>T NG_007148.3:g.102262G>A LRG_1205:g.102262G>A LRG_1205t1:c.208G>A LRG_1205p1:p.Asp70Asn O43520:p.Asp70Asn - Protein change
- D70N
- Other names
- -
- Canonical SPDI
- NC_000018.10:57706560:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
0.00180 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00141
1000 Genomes Project 0.00180
The Genome Aggregation Database (gnomAD) 0.00245
Trans-Omics for Precision Medicine (TOPMed) 0.00257
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. |
|||
ATP8B1 | - | - |
GRCh38 GRCh37 |
506 | 1074 |
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. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Mar 25, 2024 | RCV000007694.9 | |
Likely benign (1) |
criteria provided, single submitter
|
Apr 26, 2017 | RCV000177233.7 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Mar 5, 2018 | RCV000661995.5 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
May 28, 2019 | RCV000661996.10 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 30, 2018 | RCV000661994.6 | |
Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2024 | RCV000952767.20 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive familial intrahepatic cholestasis type 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001285582.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
Benign
(Jun 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000577533.4
First in ClinVar: Jun 29, 2015 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 15888793, 4260417, 28733223, 19731236, 20981092, 15239083, 22995991, 24627769, 24260417, 27884173, 23891399, 32917322)
|
|
Likely benign
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001099294.4
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
|
|
Likely benign
(Apr 26, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000229075.5
First in ClinVar: Jun 29, 2015 Last updated: Jun 29, 2015 |
Number of individuals with the variant: 7
Sex: mixed
|
|
Uncertain significance
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive familial intrahepatic cholestasis type 1
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001140913.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
Uncertain significance
(Jul 30, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Benign recurrent intrahepatic cholestasis type 1
Affected status: yes
Allele origin:
maternal
|
Baylor Genetics
Accession: SCV001528420.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
Uncertain significance
(Mar 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive familial intrahepatic cholestasis
Affected status: yes
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000784328.2
First in ClinVar: Jul 13, 2018 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Geographic origin: Iran
|
|
Uncertain significance
(Mar 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive familial intrahepatic cholestasis type 2
Affected status: yes
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000784327.2
First in ClinVar: Jul 13, 2018 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Geographic origin: Iran
|
|
Uncertain significance
(Mar 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Benign recurrent intrahepatic cholestasis type 1
Affected status: yes
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000784326.2
First in ClinVar: Jul 13, 2018 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Geographic origin: Iran
|
|
Uncertain significance
(Mar 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cholestasis of pregnancy
Affected status: yes
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000784325.2
First in ClinVar: Nov 10, 2016 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Geographic origin: Iran
|
|
Benign
(Mar 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cholestasis, intrahepatic, of pregnancy, 1
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806079.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
|
Likely benign
(Feb 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002498382.12
First in ClinVar: Apr 08, 2022 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
|
|
Pathogenic
(Jun 01, 2005)
|
no assertion criteria provided
Method: literature only
|
CHOLESTASIS, INTRAHEPATIC, OF PREGNANCY, 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000027895.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 01, 2016 |
Comment on evidence:
In 3 unrelated patients with intrahepatic cholestasis of pregnancy-1 (ICP1; 147480), Mullenbach et al. (2005) identified a heterozygous 208G-A transition in exon 2 of the … (more)
In 3 unrelated patients with intrahepatic cholestasis of pregnancy-1 (ICP1; 147480), Mullenbach et al. (2005) identified a heterozygous 208G-A transition in exon 2 of the ATP8B1 gene, resulting in an asp70-to-asn (D70N) substitution. The D70N mutation was not identified in 120 healthy pregnant women. Klomp et al. (2004) identified the D70N substitution in 0.5% of control chromosomes. (less)
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001549529.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The ATP8B1 p.D70N variant was identified in the literature in 8 heterozygous individuals with chronic pancreatitis, 3 heterozygous individuals with intrahepatic cholestasis of pregnancy, two … (more)
The ATP8B1 p.D70N variant was identified in the literature in 8 heterozygous individuals with chronic pancreatitis, 3 heterozygous individuals with intrahepatic cholestasis of pregnancy, two compound heterozygous individuals with benign recurrent intrahepatic cholestasis, a heterozygous individual with ‘low-normal’ gamma glutamyl transpeptidase (gGT) cholestasis and two heterozygous individuals with liver injury; this variant was also reported as a heterozygous variant in 9 healthy controls (Mullenbach_2005_PMID:15888793; Klomp_2004_PMID:15239083; Van der Woerd_2013_PMID:24260417; McKay_2013_PMID:24627769; Giovannoni_2015_PMID:26678486; Stolz_2019_PMID:30934130). The variant was identified in dbSNP (ID: rs34719006) and ClinVar (classified as uncertain significance by GeneDx, Illumina, Mendelics and Genomic Research Centre, Shihad Beheshti University of Medical Sciences; as likely benign by EGL Genetic Diagnostics and Invitae; and as pathogenic by OMIM). The variant was identified in control databases in 877 of 282502 chromosomes (2 homozygous) at a frequency of 0.003104, and was observed at the highest frequency in the European (non-Finnish) population in 567 of 129006 chromosomes (freq: 0.004395) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.D70 residue is conserved in mammals however computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not very predictive of pathogenicity. In vitro functional analysis reveals that the p.D70N variant does not affect protein localization and has residual activity compared to wildtype (Folmer_2009_PMID:19731236; Takatsu_2014_PMID:25315773). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
An informatics approach to analyzing the incidentalome. | Berg JS | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22995991 |
A map of human genome variation from population-scale sequencing. | 1000 Genomes Project Consortium | Nature | 2010 | PMID: 20981092 |
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 |
ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy. | Müllenbach R | Gut | 2005 | PMID: 15888793 |
Characterization of mutations in ATP8B1 associated with hereditary cholestasis. | Klomp LW | Hepatology (Baltimore, Md.) | 2004 | PMID: 15239083 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATP8B1 | - | - | - | - |
Text-mined citations for rs34719006 ...
HelpRecord last updated Apr 15, 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.