Overview

Clinical Phenotype: Cerebral Palsy, Blood Lipids/Lipoproteins, Cardiovascular Disease
Position: (GRCh38/hg38):Chr19:44909083 G>A
Position: (GRCh37/hg19):Chr19:45412340 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs190853081
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAG to AAG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant is one of two contiguous substitutions of glutamates by lysines in the E262_E263delinsKK (Suita) variant. The Suita variant is associated with increased plasma lipid levels and cardiovascular disease (for additional information on the double substitution go to the Suita detail page).

In addition, the major allele E263 was reported as a component of a group of five APOE variants, a haplotype, associated with decreased risk for cerebral palsy in a Chinese cohort including 350 patients and 242 controls (OR=2.06, 95% CI [1.20-3.53], p=0.035; Xu et al., 2014). Six infants with cerebral palsy had the E263K variant, whereas none of the controls did.

In the gnomAD variant database, this variant was found only in East Asians at a frequency of 0.003 (gnomAD v2.1.1, Sep 2022).

Biological Effect

The biological effect of this variant is unknown. However, it has been noted that E263 likely helps shield the receptor-binding region of ApoE in the absence of bound lipids by forming salt bridges with R162 and R165, both in the receptor binding region. Altering E263’s charge could destabilize these interactions, favoring premature binding of lipid-free ApoE to receptors (Zhou et al., 2018).

Also, a study analyzing whole-genome and whole-exome sequencing data from 138,632 individuals, identified E263K as one of six APOE variants likely to have functional consequences and clinical relevance given their high prevalence in at least one population and their classification by five algorithms (SIFT, Polyphen2, MutationAssessor, PROVEAN, and DANN) as deleterious with high confidence (Zhou et al., 2018). Consistent with this finding, additional in silico algorithms classified the substitution as damaging (Nagahara et al., 2021 /papers/genetic-analysis-japanese-children-clinically-diagnosed-familial-hypercholesterolemia), and its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (23.9; CADD v.1.6, Oct 2022).

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References

Mutations Citations

1. APOE E262_E263delinsKK (Suita)

Paper Citations

1. Xu Y, Wang H, Sun Y, Shang Q, Chen M, Li T, Zhu D, He L, Zhu C, Xing Q. The association of apolipoprotein E gene polymorphisms with cerebral palsy in Chinese infants. Mol Genet Genomics. 2014 Jun;289(3):411-6. Epub 2014 Feb 13 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.

Further Reading

No Available Further Reading