Incidentalome

Gene: APOE

Green List (high evidence)

APOE (apolipoprotein E)
EnsemblGeneIds (GRCh38): ENSG00000130203
EnsemblGeneIds (GRCh37): ENSG00000130203
OMIM: 107741, Gene2Phenotype
APOE is in 8 panels

3 reviews

Elena Savva (Victorian Clinical Genetics Services)

I don't know

E4 is a risk factor for Alzheimer’s disease and has the Cys130Arg variant
Cys130Arg has 24455 hets and 2091 homs in gnomAD

E4 allele appears to act as a risk factor

Likely toxic GOF- PMID: 33679311 talks about the E4 allele being poorly lipidated because it has reduced binding affinity for HDL. This greater proportion of unlipidated APOE forms aggregates that are toxic to neurons.
Created: 31 Mar 2022, 11:49 p.m. | Last Modified: 31 Mar 2022, 11:49 p.m.
Panel Version: 0.154

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Alzheimer disease 2 MIM#104310

Publications

Mode of pathogenicity
Other

Lucy Spencer (Victorian Clinical Genetics Services)

Green List (high evidence)

PMID: 27014949- The leu167del variant has also been associated with hypercholesterolaemia, it only has 3 hets 0 homs in v2. It has been seen to segregate in several families with autosomal dominant hypercholesterolemia.

PMID: 34058468 also lists many more variants have been previously reported and associated with a range of dyslipoproteinemias in table 1. Arg163Cys was seen to segregate in a het mother with raised LDL cholesterol and in her homozygote son who had even higher LDL cholesterol. Leu167del and 2 other missense variant have also been seen to segregate in families with familial combined hyperlipidemia.

There is also a lot of talk in the literature about the 3 main alleles of APOE- E3 is wild type with Cys130 (previously 112) and Arg176 (previously 158) (PMID: 33679311).
The E2 allele (with the Arg176Cys variant) has been associated with hyperlipoproteinemia, type III when homozygous, but it seems to be essentially only a risk factor and only causes disease in the presence of other environmental/genetic risk factors (PMID: 34058468). E2 is also a protective factor against Alzheimer’s.
E4 is a risk factor for alzhiemers disease and has the Cys130Arg variant, it is also associated with increased LDL cholesterol levels and thus associated with cardiovascular disease risk (PMID: 34058468).
However it is worth noting that the Arg176Cys variant has 10,066 hets and 465 homs in gnomad v2, and Cys130Arg has 24,455 hets and 2091 homs.

Therefore it seems like there are some risk factor variant in APOE that are very high in the population, but also some genuine variants with reasonable population counts that are associated with a range of hypercholesterolaemias/dyslipoproteinemias.
Created: 30 Mar 2022, 10:23 p.m. | Last Modified: 30 Mar 2022, 10:24 p.m.
Panel Version: 0.22

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Hyperlipoproteinemia, type III (MIM#617347); Sea-blue histiocyte disease (MIM#269600)

Publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

I don't know

E4 allele association with late-onset AD. Susceptibility allele.
Created: 25 Sep 2020, 12:10 a.m. | Last Modified: 1 Jun 2022, 7:26 a.m.
Panel Version: 0.154

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Alzheimer disease 2, MIM# 104310

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Victorian Clinical Genetics Services
  • Melbourne Genomics Health Alliance Complex Neurology Flagship
  • Victorian Clinical Genetics Services
Phenotypes
  • Alzheimer disease 2, MIM# 104310
  • Hyperlipoproteinemia, type III (MIM#617347)
  • Sea-blue histiocyte disease (MIM#269600)
Tags
adult onset neurodegenerative
OMIM
107741
Clinvar variants
Variants in APOE
Penetrance
None
Publications
Panels with this gene

History Filter Activity

15 Aug 2024, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: apoe has been classified as Green List (High Evidence).

15 Aug 2024, Gel status: 3

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: APOE were set to

15 Aug 2024, Gel status: 3

Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Mode of inheritance for gene: APOE was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

21 Aug 2023, Gel status: 3

Set Phenotypes

Bryony Thompson (Royal Melbourne Hospital)

Phenotypes for gene: APOE were changed from Alzheimer disease 2, MIM# 104310 to Alzheimer disease 2, MIM# 104310; Hyperlipoproteinemia, type III (MIM#617347); Sea-blue histiocyte disease (MIM#269600)

21 Aug 2023, Gel status: 3

Added Tag

Bryony Thompson (Royal Melbourne Hospital)

Tag adult onset neurodegenerative tag was added to gene: APOE.

21 Aug 2023, Gel status: 3

Set Phenotypes

Bryony Thompson (Royal Melbourne Hospital)

Phenotypes for gene: APOE were changed from to Alzheimer disease 2, MIM# 104310

17 Nov 2019, Gel status: 3

Created, Added New Source, Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

gene: APOE was added gene: APOE was added to Incidentalome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: APOE was set to Unknown