Overview

Clinical Phenotype: Alzheimer's Disease, Blood Lipids/Lipoproteins, Cardiovascular Disease
Position: (GRCh38/hg38):Chr19:44907894 A>G
Position: (GRCh37/hg19):Chr19:45411151 A>G
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs28931576
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACA to GCA
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 3

Findings

This variant was found in an individual with Alzheimer’s disease (AD) who also carried the L46P mutation (Scacchi et al., 2003). No further data on its relationship to AD has been reported.

The variant was first identified in a study of Caucasian Germans in Freiburg (Wieland et al., 1991). It was named APOE3-Freiburg because its encoded protein migrates to a slightly more acidic position than the common isoform APOE3 upon isoelectric focusing. The authors noted it “did not appear to be associated with either lipid disorders or heart disease,” but the number of carriers identified in the study was not specified.

As reported in the gnomAD database, the global frequency of this variant is 0.000012, with three alleles found in European, non-Finnish individuals and none reported in individuals of other ancestries (gnomAD v2.1.1, Apr 2022).

Biological Effect

The biological effect of this variant is unknown. T60 has been suggested to stabilize dimerization of ApoE2 and ApoE3, but not ApoE4, by interacting with Q141 (Nemergut et al., 2023). However, T60A results in the substitution of one uncharged amino acid, threonine, by another, alanine, which is predicted to be benign (Polyphen) and tolerated (SIFT) (gnomAD v2.1.1, Feb 2021). Its PHRED-scaled CADD score, which integrates diverse information in silico, did not reach 20, a commonly used threshold to predict deleteriousness (CADD v.1.6, Apr 2022).

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Mutations Citations

1. APOE L46P

Paper Citations

1. Scacchi R, Gambina G, Ferrari G, Corbo RM. Screening of two mutations at exon 3 of the apolipoprotein E gene (sites 28 and 42) in a sample of patients with sporadic late-onset Alzheimer's disease. Neurobiol Aging. 2003 Mar-Apr;24(2):339-43. PubMed.
2. 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.
3. Nemergut M, Marques SM, Uhrik L, Vanova T, Nezvedova M, Gadara DC, Jha D, Tulis J, Novakova V, Planas-Iglesias J, Kunka A, Legrand A, Hribkova H, Pospisilova V, Sedmik J, Raska J, Prokop Z, Damborsky J, Bohaciakova D, Spacil Z, Hernychova L, Bednar D, Marek M. Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer's Disease drug candidate. Mol Neurodegener. 2023 Jun 6;18(1):38. PubMed.

Further Reading

No Available Further Reading