Overview

Clinical Phenotype: Alzheimer's Disease, Cardiovascular Disease
Reference Assembly: GRCh37/hg19
Position: Chr19:45411025 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs533904656
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCC to ACC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 3

Findings

This variant was reported in a small study in which the APOE genes of 257 Southern Chinese individuals, including 69 AD patients, 83 subjects with mild cognitive impairment (MCI), and 105 cognitively healthy controls, were sequenced (Yee et al., 2021). The variant was found in one AD patient (0.7%), three MCI patients (1.8%), and four controls (1.9%). 

The variant was also identified in a study of cardiovascular disease risk as one of six APOE variants likely to have functional consequences and clinical relevance given its high prevalence in at least one population and its predicted deleterious effects as assessed by several in silico algorithms (Zhou et al., 2018). The study analyzed whole-genome and whole-exome sequencing data from 138,632 individuals, including non-Finnish Europeans, Finnish, Africans, East Asians, South Asians, Latinos, Ashkenazi Jews, and members of other populations.

Although this variant is very rare worldwide, its frequency in East Asians is higher. In the gnomAD variant database, 39 of 41 heterozygotic carriers were of East Asian ancestry (gnomAD v2.1.1 Apr 2022).

Biological Effect

This variant alters the ApoE signal peptide sequence at its cleavage site and has been predicted to disrupt cleavage-site recognition, potentially affecting ApoE secretory efficiency (Zhou et al., 2018, Yee et al., 2021). It was predicted to be deleterious by several algorithms (Zhou et al., 2018; Pires et al., 2017 see supplementary table 2). Consistent with these predictions, this variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Apr 2022).

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References

Paper Citations

1. Yee A, Tsui NB, Kwan RY, Leung AY, Lai CK, Chung T, Lau JY, Fok M, Dai DL, Lau LT. Apolipoprotein E Gene Revisited: Contribution of Rare Variants to Alzheimer's Disease Susceptibility in Southern Chinese. Curr Alzheimer Res. 2021 Mar 24; PubMed.
2. Zhou Y, Mägi R, Milani L, Lauschke VM. Global genetic diversity of human apolipoproteins and effects on cardiovascular disease risk. J Lipid Res. 2018 Oct;59(10):1987-2000. Epub 2018 Aug 3 PubMed.
3. Pires AS, Porto WF, Franco OL, Alencar SA. In silico analyses of deleterious missense SNPs of human apolipoprotein E3. Sci Rep. 2017 May 30;7(1):2509. PubMed.

Further Reading

No Available Further Reading