Overview

Position: (GRCh38/hg38):Chr19:44908804 G>C
Position: (GRCh37/hg19):Chr19:45412061 G>C
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs267606662
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCC to CCC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was found in mRNA from the liver of a 57-year-old trauma victim who died of cardiac arrest during surgery (McLean et al., 1984). No medical history was available, but signs of hyperlipidemia were reported in some family members (Lalazar et al., 1988). Two of three cDNAs derived from the patient’s mRNA corresponded to the common APOE3 allele, but the third included five unique variants: A170P, A99T, and three silent substitutions in V103, S241, and Q266 (McLean et al., 1984). The authors suspected A170P could be of clinical relevance given that it borders the ApoE receptor binding site.

Biological Effect

An in vitro assay, using a bacterial-expressed mutant ApoE, revealed a 73 percent reduction in this variant’s binding to low-density lipoprotein receptors (LDLRs) compared with ApoE3 (Lalazar et al., 1988).

However, the A170P substitution does not result in a change in charge and its PHRED-scaled CADD score (15.85), which integrates diverse information in silico, did not reach 20, a commonly used threshold to predict deleteriousness (CADD v.1.6, May 2022).

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References

Paper Citations

1. McLean JW, Elshourbagy NA, Chang DJ, Mahley RW, Taylor JM. Human apolipoprotein E mRNA. cDNA cloning and nucleotide sequencing of a new variant. J Biol Chem. 1984 May 25;259(10):6498-504. PubMed.
2. Lalazar A, Weisgraber KH, Rall SC Jr, Giladi H, Innerarity TL, Levanon AZ, Boyles JK, Amit B, Gorecki M, Mahley RW. Site-specific mutagenesis of human apolipoprotein E. Receptor binding activity of variants with single amino acid substitutions. J Biol Chem. 1988 Mar 15;263(8):3542-5. PubMed.

Further Reading

No Available Further Reading