Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIa
Position: (GRCh38/hg38):Chr19:44909104_44909105 CT>GA
Position: (GRCh37/hg19):Chr19:45412361_45412362 CT>GA
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Deletion-Insertion
Expected RNA Consequence: Deletion-Insertion
Expected Protein Consequence: Missense
Codon Change: CTG to GAG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was described in a 38-year-old Caucasian woman in Germany diagnosed with hyperlipoproteinemia type IIa (HLPP2a), a condition characterized by very high low-density lipoprotein (LDL) cholesterol levels in blood (van den Maagdenberg et al., 1993). Although patients with HLPP2a often have early onset coronary heart disease, she had no evidence of either this ailment or peripheral vascular disease.

The carrier’s ApoE proteins migrated on an isoelectric focusing gel to the known position of the common ApoE3 isoform and to a position beyond ApoE3 and R176C (ApoE2), corresponding to a more acidic composition described as ApoE1. Sequencing revealed a wildtype APOE3 allele and an APOE2 allele with an additional dinucleotide change resulting in the L270E variant. The mutation was also identified, indirectly by isoelectric focusing, in one of the proband’s two daughters who was 12 years old. Like her mother, the girl had elevated levels of total cholesterol, while her triglyceride levels were in the normal range.

The variant was absent from the gnomAD variant database (v2.1.1, June 2022).

Biological Effect

The biological effect of this variant is unknown, but it might alter ApoE’s interactions with lipids since it lies in the lipid-binding region.

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References

Paper Citations

1. van den Maagdenberg AM, Weng W, de Bruijn IH, de Knijff P, Funke H, Smelt AH, Gevers Leuven JA, van't Hooft FM, Assmann G, Hofker MH. Characterization of five new mutants in the carboxyl-terminal domain of human apolipoprotein E: no cosegregation with severe hyperlipidemia. Am J Hum Genet. 1993 May;52(5):937-46. PubMed.

Further Reading

No Available Further Reading