ClinVar Genomic variation as it relates to human health
NM_000041.3(APOE):c.[137T>C;388T>C]
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.[137T>C;388T>C]
- Other names
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APOE, LEU28PRO AND CYS112ARG
- Functional consequence
- Uncertain function
- Links
- ClinGen: CA041979
- OMIM: 107741.0023
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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| APOE | - | - |
GRCh38 GRCh37 |
189 | 208 | |
Conditions - Germline
| Condition
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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
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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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APOE4(-)-FREIBURG
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Pathogenic (1) |
no assertion criteria provided
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Feb 15, 2017 | RCV000019456.38 |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 27, 2020 | RCV001175124.10 |
Submissions - Germline
| Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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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|---|---|---|---|---|---|
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Pathogenic
(Feb 15, 2017)
|
no assertion criteria provided
Method: literature only
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APOE4(-)-FREIBURG
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000039746.3
First in ClinVar: Apr 04, 2013 Last updated: Feb 18, 2017 |
Comment on evidence:
Wieland et al. (1991) identified an apolipoprotein E4 variant in German-Caucasian subjects that was not associated with hyperlipidemia. The variant was designated E4(-) because it … (more)
Wieland et al. (1991) identified an apolipoprotein E4 variant in German-Caucasian subjects that was not associated with hyperlipidemia. The variant was designated E4(-) because it is slightly more acidic than E4 (107741.0016). This variant has a leu28-to-pro substitution (CTG-to-CCG). (less)
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Likely pathogenic
(May 27, 2020)
|
no assertion criteria provided
Method: clinical testing
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
GBinsight Genetic Testing by GB HealthWatch, Genben Lifesciences Corporation
Accession: SCV001321553.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Multiple, unrelated, probands were referred, from independent clinics, for clinical genetic testing for familial hypercholesterolemia. Clinical genetic testing identified heterozygosity for the APOE4(-)-FREIBURG haplotype consisting … (more)
Multiple, unrelated, probands were referred, from independent clinics, for clinical genetic testing for familial hypercholesterolemia. Clinical genetic testing identified heterozygosity for the APOE4(-)-FREIBURG haplotype consisting of p.Cys130Arg (E4) AND p.Leu46Pro genetic variants in the germline. Amongst these, all had the haplotype. Phenotype segregated with genotype in the families tested. (less)
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Germline Functional Evidence
| Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain function
Uncertain function
Uncertain function
|
GBinsight Genetic Testing by GB HealthWatch, Genben Lifesciences Corporation
Accession: SCV001321553.1
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Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. | Montagne A | Nature | 2020 | PMID: 32376954 |
| LIPA gene mutations affect the composition of lipoproteins: Enrichment in ACAT-derived cholesteryl esters. | Arnaboldi L | Atherosclerosis | 2020 | PMID: 32058863 |
| Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease. | Ruskey JA | European journal of medical genetics | 2019 | PMID: 29842932 |
| Differential burden of rare protein truncating variants in Alzheimer's disease patients compared to centenarians. | Freudenberg-Hua Y | Human molecular genetics | 2016 | PMID: 27260402 |
| Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France. | Wintjens R | Journal of lipid research | 2016 | PMID: 26802169 |
| Molecular basis for increased risk for late-onset Alzheimer disease due to the naturally occurring L28P mutation in apolipoprotein E4. | Argyri L | The Journal of biological chemistry | 2014 | PMID: 24644280 |
| Personalized genomic disease risk of volunteers. | Gonzalez-Garay ML | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 24082139 |
| Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans. | Reitz C | JAMA | 2013 | PMID: 23571587 |
| Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. | Liu CC | Nature reviews. Neurology | 2013 | PMID: 23296339 |
| APOE4-specific changes in Aβ accumulation in a new transgenic mouse model of Alzheimer disease. | Youmans KL | The Journal of biological chemistry | 2012 | PMID: 23060451 |
| Association between apolipoprotein E gene polymorphism and the risk of vascular dementia: a meta-analysis. | Yin YW | Neuroscience letters | 2012 | PMID: 22381401 |
| Aggregation of α-synuclein in brain samples from subjects with glucocerebrosidase mutations. | Choi JH | Molecular genetics and metabolism | 2011 | PMID: 21742527 |
| Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. | Sidransky E | The New England journal of medicine | 2009 | PMID: 19846850 |
| Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. | Caselli RJ | The New England journal of medicine | 2009 | PMID: 19605830 |
| Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset. | Nichols WC | Neurology | 2009 | PMID: 18987351 |
| Phenotypic heterogeneity of N370S homozygotes with type I Gaucher disease: an analysis of 798 patients from the ICGG Gaucher Registry. | Fairley C | Journal of inherited metabolic disease | 2008 | PMID: 18979180 |
| Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). | Hruska KS | Human mutation | 2008 | PMID: 18338393 |
| Structural and phylogenetic approaches to assess the significance of human Apolipoprotein E variation. | Corbo RM | Molecular genetics and metabolism | 2006 | PMID: 16621646 |
| APOE genotype and cognitive decline in a middle-aged cohort. | Blair CK | Neurology | 2005 | PMID: 15668424 |
| Impact of APOE in mild cognitive impairment. | Farlow MR | Neurology | 2004 | PMID: 15557508 |
| APOE-epsilon4 predicts dementia but not other psychiatric disorders after traumatic brain injury. | Koponen S | Neurology | 2004 | PMID: 15326261 |
| Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele. | Caselli RJ | Neurology | 2004 | PMID: 15184602 |
| Functional analysis of 13 GBA mutant alleles identified in Gaucher disease patients: Pathogenic changes and "modifier" polymorphisms. | Montfort M | Human mutation | 2004 | PMID: 15146461 |
| Accelerated evolution of brain atrophy and "black holes" in MS patients with APOE-epsilon 4. | Enzinger C | Annals of neurology | 2004 | PMID: 15048896 |
| ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo. | DeMattos RB | Neuron | 2004 | PMID: 14741101 |
| APOE genotype influences acquisition and recall following traumatic brain injury. | Crawford FC | Neurology | 2002 | PMID: 11940706 |
| Apolipoprotein E epsilon 4 and short-term recovery from predominantly mild brain injury. | Liberman JN | Neurology | 2002 | PMID: 11940689 |
| Accelerated hippocampal atrophy in Alzheimer's disease with apolipoprotein E epsilon4 allele. | Mori E | Annals of neurology | 2002 | PMID: 11835377 |
| Characterization of transgenic mice expressing apolipoprotein E4(C112R) and apolipoprotein E4(L28P; C112R). | Huber G | Neuroscience | 2000 | PMID: 11068149 |
| Dominant negative effects of apolipoprotein E4 revealed in transgenic models of neurodegenerative disease. | Buttini M | Neuroscience | 2000 | PMID: 10799751 |
| A novel mutation in the apolipoprotein E gene (APOE*4 Pittsburgh) is associated with the risk of late-onset Alzheimer's disease. | Kamboh MI | Neuroscience letters | 1999 | PMID: 10213152 |
| Apolipoprotein E-epsilon4 genotype predicts a poor outcome in survivors of traumatic brain injury. | Friedman G | Neurology | 1999 | PMID: 9932938 |
| Association of apolipoprotein E polymorphism with outcome after head injury. | Teasdale GM | Lancet (London, England) | 1997 | PMID: 10213549 |
| Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. | Farrer LA | JAMA | 1997 | PMID: 9343467 |
| Relative risk of Alzheimer disease and age-at-onset distributions, based on APOE genotypes among elderly African Americans, Caucasians, and Hispanics in New York City. | Tang MX | American journal of human genetics | 1996 | PMID: 8644717 |
| Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham study. | Myers RH | Neurology | 1996 | PMID: 8618665 |
| Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression. | Grace ME | The Journal of biological chemistry | 1994 | PMID: 8294487 |
| Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. | Saunders AM | Neurology | 1993 | PMID: 8350998 |
| Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. | Corder EH | Science (New York, N.Y.) | 1993 | PMID: 8346443 |
| Genetic heterogeneity in type 1 Gaucher disease: multiple genotypes in Ashkenazic and non-Ashkenazic individuals. | Tsuji S | Proceedings of the National Academy of Sciences of the United States of America | 1988 | PMID: 3353383 |
| Isolation, characterization, and mapping to chromosome 19 of the human apolipoprotein E gene. | Das HK | The Journal of biological chemistry | 1985 | PMID: 3922972 |
| Nucleotide sequence and structure of the human apolipoprotein E gene. | Paik YK | Proceedings of the National Academy of Sciences of the United States of America | 1985 | PMID: 2987927 |
| Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. | Weisgraber KH | The Journal of biological chemistry | 1981 | PMID: 7263700 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=APOE | - | - | - | - |
| Wieland, H., Funke, H., Krieg, J., Luley, C. ApoE3-Freiburg and apoE4-Freiburg are two genetic apoE variants which are caused by exchanges of uncharged amino acids and do not appear to be associated with lipid disorders or heart disease. Abstract Book of the Ninth International Symposium on Atherosclerosis. Rosemont, Illinois 1991. P. 164. | - | - | - | - |
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Text-mined citations for this variant ...
HelpRecord last updated Oct 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.