Overview

Clinical Phenotype: Alzheimer's Disease, Blood Lipids/Lipoproteins, Dementia
Reference Assembly: GRCh37/hg19
Position: Chr19:45409912 A>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs144354013
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACA to TCA
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 2

Findings

This variant was examined in a study of dementia, including Alzheimer’s disease (Rasmussen et al., 2020). In two cohorts totaling more than 100,000 individuals from Copenhagen, Denmark, the variant was found in 29 individuals, 17 who were at least 60 years old, none of whom had dementia (3.26 percent of non-carriers had dementia).

In the 29 carriers, mean plasma levels of ApoE and several lipid species, including cholesterol in low-density lipoprotein particles (LDL-C), remnant cholesterol, cholesterol in high-density lipoprotein particles (HDL-C), and triglycerides, were within normal ranges (Rasmussen et al., 2020, Rasmussen et al., 2023). However, 24 percent of the carriers were on a lipid-lowering therapy compared with 11 percent in the overall population.

The variant was found in carriers of the APOE4 allele more frequently than in non-carriers. Seventeen percent of T11S carriers were homozygous for APOE4 (versus three percent in the overall population of the two cohorts), 66 percent were APOE3/APOE4 heterozygotes (versus 26 percent), and 17 percent were APOE2/APOE4 heterozygotes (versus three percent).

The frequency of T11S in the gnomAD variant database is 0.000014 (v2.1.1, Apr 2022), lower than the 0.00027 frequency reported in the Danish study (Rasmussen et al., 2020). Interestingly, the four carriers reported in gnomAD were all of Latino/Admixed ancestry.

Biological Effect

The biological effect of this variant is unknown. It is located in the signal peptide of ApoE which does not form part of the mature protein.

This variant’s PHRED-scaled CADD score, which integrates diverse information in silico, was very low (0.586), far below the commonly used threshold of 20 to predict deleteriousness (CADD v.1.6, Oct 2021).

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References

Paper Citations

1. Rasmussen KL, Tybjaerg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. APOE and dementia - resequencing and genotyping in 105,597 individuals. Alzheimers Dement. 2020 Dec;16(12):1624-1637. Epub 2020 Aug 18 PubMed.
2. Rasmussen KL, Luo J, Nordestgaard BG, Tybjærg-Hansen A, Frikke-Schmidt R. APOE and vascular disease: Sequencing and genotyping in general population cohorts. Atherosclerosis. 2023 Nov;385:117218. Epub 2023 Aug 9 PubMed.

Further Reading

No Available Further Reading