ClinVar Genomic variation as it relates to human health
NM_000041.2(APOE):c.526C>T (p.Arg176Cys)
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
- NM_000041.3(APOE):c.[434G>A;526C>T]
- NM_000041.3(APOE):c.[526C>T;725G>A]
- NM_000041.3(APOE):c.[526C>T;761T>A]
- Identifiers
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NM_000041.2(APOE):c.526C>T (p.Arg176Cys)
Variation ID: 17848 Accession: VCV000017848.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.32 19: 44908822 (GRCh38) [ NCBI UCSC ] 19: 45412079 (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 May 22, 2016 May 12, 2024 Mar 24, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000041.4:c.526C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000032.1:p.Arg176Cys missense NM_001302688.2:c.604C>T NP_001289617.1:p.Arg202Cys missense NM_001302689.2:c.526C>T NP_001289618.1:p.Arg176Cys missense NM_001302690.2:c.526C>T NP_001289619.1:p.Arg176Cys missense NM_001302691.2:c.526C>T NP_001289620.1:p.Arg176Cys missense NC_000019.10:g.44908822C>T NC_000019.9:g.45412079C>T NG_007084.2:g.8041C>T P02649:p.Arg176Cys - Protein change
- R176C, R202C
- Other names
- R158C
- R148C
- Canonical SPDI
- NC_000019.10:44908821:C:T
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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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0.07508 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.07182
1000 Genomes Project 0.07508
1000 Genomes Project 30x 0.07714
Trans-Omics for Precision Medicine (TOPMed) 0.07812
The Genome Aggregation Database (gnomAD) 0.07986
The Genome Aggregation Database (gnomAD), exomes 0.06150
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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APOE | - | - |
GRCh38 GRCh37 |
175 | 195 |
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 (1) |
no assertion criteria provided
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Oct 1, 2005 | RCV000019428.38 | |
drug response (1) |
reviewed by expert panel
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Mar 24, 2021 | RCV000211178.12 | |
Likely benign; other; risk factor (5) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2023 | RCV000346955.22 | |
drug response (1) |
no assertion criteria provided
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Aug 31, 2010 | RCV000845582.10 | |
Benign (1) |
criteria provided, single submitter
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Jan 1, 2019 | RCV001262472.9 | |
Benign (1) |
no assertion criteria provided
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- | RCV001529800.10 |
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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drug response
Drug-variant association: Efficacy
(Mar 24, 2021)
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reviewed by expert panel
Method: curation
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atorvastatin response - Efficacy
Drug used for
Coronary Disease
, and Hyperlipidemias
Affected status: yes
Allele origin:
germline
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PharmGKB
Accession: SCV000268391.4
First in ClinVar: May 22, 2016 Last updated: Dec 12, 2021
Comment:
Drug is not necessarily used to treat response condition
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Comment:
PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with … (more)
PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications. (less)
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other
(Feb 11, 2016)
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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: SCV000333416.3
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 1
Sex: mixed
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Benign
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440366.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Likely benign
(Aug 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004033681.6
First in ClinVar: Sep 16, 2023 Last updated: May 12, 2024 |
Comment:
APOE: PM5, BS1, BS2
Number of individuals with the variant: 1
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risk factor
(-)
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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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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987597.1
First in ClinVar: Sep 09, 2019 Last updated: Sep 09, 2019 |
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Pathogenic
(Oct 01, 2005)
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no assertion criteria provided
Method: literature only
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HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE2, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039717.5
First in ClinVar: Apr 04, 2013 Last updated: Jan 24, 2018 |
Comment on evidence:
Apolipoprotein E2 exists in 2 main isoforms, arg158 and cys158 (Rall et al., 1982; Gill et al., 1985). The second isoform (arg158-to-cys; R158C) was found … (more)
Apolipoprotein E2 exists in 2 main isoforms, arg158 and cys158 (Rall et al., 1982; Gill et al., 1985). The second isoform (arg158-to-cys; R158C) was found in 98 of 100 E2 alleles by Emi et al. (1988). The other isoforms that give a band at the E2 position with isoelectric focusing include E2(lys146-to-gln) (107741.0011) and E2(arg145-to-cys; 107741.0004). Type III hyperlipoproteinemia is typically associated with homozygosity for a change in apolipoprotein E2 from arg158 to cys. By generating mice with a human APOE*2 allele in place of the mouse Apoe gene via targeted gene replacement in embryonic stem cells, Sullivan et al. (1998) demonstrated that a single amino acid difference (R158C) in the APOE protein is sufficient to cause type III hyperlipoproteinemia and spontaneous atherosclerosis in mice. Mice expressing human APOE2 (2/2) had virtually all the characteristics of type III hyperlipoproteinemia. Both their plasma cholesterol and triglyceride levels were 2 to 3 times those in normolipidemic mice that expressed human APOE3 (3/3) generated in an identical manner. The 2/2 mice were markedly defective in clearing beta-migrating VLDL particles and spontaneously developed atherosclerotic plaques, even on a regular diet. An atherogenic diet, high in fat and cholesterol, exacerbated development of atherosclerosis and xanthomas in the 2/2 mice. In 72 patients with type III hyperlipidemia (617347) and the APOE 2/2 genotype, Evans et al. (2005) found a significantly higher frequency for at least 1 minor allele of the APOA5 -1131T-C and S19W (606368.0002) SNPs in patients than in controls (53% vs 19.7%, respectively; p = 0.0001). Evans et al. (2005) concluded that genetic variation in the APOA5 gene is an important cofactor in the development of type III hyperlipidemia. (less)
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drug response
(Aug 31, 2010)
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no assertion criteria provided
Method: research
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Warfarin response
Drug used for
hemorrhage
Affected status: no
Allele origin:
unknown
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Pharmacogenomics Lab, Chungbuk National University
Accession: SCV000889947.1
First in ClinVar: Sep 09, 2019 Last updated: Sep 09, 2019 |
Number of individuals with the variant: 19
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001743895.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926324.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550093.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The APOE p.Arg176Cys variant, also known as the APOE ε2 allele, was identified in dbSNP (ID: rs7412), ClinVar (reported by EGL Genetics in relation to … (more)
The APOE p.Arg176Cys variant, also known as the APOE ε2 allele, was identified in dbSNP (ID: rs7412), ClinVar (reported by EGL Genetics in relation to drug metabolism), Clinvitae, MutDB and LOVD 3.0. The variant was identified in control databases in 10996 of 168078 chromosomes (465 homozygous) at a frequency of 0.065422 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1632 of 15264 chromosomes (freq: 0.1069), Ashkenazi Jewish in 664 of 8410 chromosomes (freq: 0.07895), European (non-Finnish) in 5202 of 67810 chromosomes (freq: 0.07671), East Asian in 947 of 12608 chromosomes (freq: 0.07511), Other in 328 of 5174 chromosomes (freq: 0.06339), European (Finnish) in 472 of 10686 chromosomes (freq: 0.04417), South Asian in 947 of 22604 chromosomes (freq: 0.0419), and Latino in 804 of 25522 chromosomes (freq: 0.0315). Homozygous individuals with the APOE ε2 genotype are at a higher risk of developing type III hyperlipoproteinemia and mouse models with the APOE ε2 genotype develop a clear type III hyperlipoproteinemia phenotype (Breslow_1982_PMID: 7175379; Sullivan_1998_PMID: 9649566). However, this variant does not show full penetrance for type III hyperlipoproteinemia and other variants in conjunction with the APOE ε2 genotype have been suggested to contribute to the phenotype (Sakuma_2014_PMID: 24953047). Another study found that carriers of the APOE ε2 allele had lower baseline LDL cholesterol levels as well as a greater reduction of LDL-C from atorvastatin and pravastatin treatment compared to APOE ε4 carriers, implicating this variant as a pharmacogenetic variant (Meg_2009_PMID: 19667110). The p.Arg176 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and BLOSUM) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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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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APOB gene polymorphisms may affect the risk of minor or minimal bleeding complications in patients on warfarin maintaining therapeutic INR. | Yee J | European journal of human genetics : EJHG | 2019 | PMID: 31186542 |
Comprehensive whole-genome and candidate gene analysis for response to statin therapy in the Treating to New Targets (TNT) cohort. | Thompson JF | Circulation. Cardiovascular genetics | 2009 | PMID: 20031582 |
Identification of genetic variants associated with response to statin therapy. | Mega JL | Arteriosclerosis, thrombosis, and vascular biology | 2009 | PMID: 19667110 |
Pharmacogenetic predictors of statin-mediated low-density lipoprotein cholesterol reduction and dose response. | Voora D | Circulation. Cardiovascular genetics | 2008 | PMID: 20031551 |
Tolerability of statins is not linked to CYP450 polymorphisms, but reduced CYP2D6 metabolism improves cholesteraemic response to simvastatin and fluvastatin. | Zuccaro P | Pharmacological research | 2007 | PMID: 17289397 |
Polymorphisms in the apolipoprotein A5 (APOA5) gene and type III hyperlipidemia. | Evans D | Clinical genetics | 2005 | PMID: 16143024 |
An association study of 43 SNPs in 16 candidate genes with atorvastatin response. | Thompson JF | The pharmacogenomics journal | 2005 | PMID: 16103896 |
Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human Apoe*2. | Sullivan PM | The Journal of clinical investigation | 1998 | PMID: 9649566 |
Genotyping and sequence analysis of apolipoprotein E isoforms. | Emi M | Genomics | 1988 | PMID: 3243553 |
Isolation and characterisation of a variant allele of the gene for human apolipoprotein E. | Gill LL | Biochemical and biophysical research communications | 1985 | PMID: 2992507 |
Identical structural and receptor binding defects in apolipoprotein E2 in hypo-, normo-, and hypercholesterolemic dysbetalipoproteinemia. | Rall SC Jr | The Journal of clinical investigation | 1983 | PMID: 6300187 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=APOE | - | - | - | - |
https://www.pharmgkb.org/clinicalAnnotation/1183492249 | - | - | - | - |
https://www.pharmgkb.org/variant/PA166155341 | - | - | - | - |
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Text-mined citations for rs7412 ...
HelpRecord last updated May 27, 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.