Overview

Clinical Phenotype: Blood Lipids/Lipoproteins, Cardiovascular Disease
Position: (GRCh38/hg38):Chr19:44908601 C>G
Position: (GRCh37/hg19):Chr19:45411858 C>G
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs11083750
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCG to CGG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was first identified by peptide sequencing in a 54-year-old woman of European descent who was part of the Framingham Offspring Study (Wardell et al., 1991). The woman had elevated low-density lipoprotein (LDL) cholesterol levels, but was asymptomatic with no evidence of either cardiovascular or cerebrovascular disease. Her 75-year-old mother had the same phenotype and there was no known history of early heart disease in the family.

As assessed by isoelectric focusing, both women had two ApoE isoforms, one that migrated similarly to the reference isoform, ApoE3, and one that migrated to position ApoE5, similar to a previously reported variant, E21K. Unlike E21K, however, this variant did not change its migration pattern after cysteamine treatment indicating it lacked a cysteine. Peptide sequencing revealed that the new variant had both a cysteine to arginine substitution at position 130, indicating the presence of the common C130R (APOE4) allele, and a proline to arginine substitution at position 102. The authors inferred the P102R substitution was due to a CCG to CGG change in the P102 codon.

This variant was also reported in 53-year-old Turkish man with severe hypertriglyceridemia (Abedi et al., 2023). Six genes involved in lipid metabolism—LPL, APOC2, APOE, APOA5, LMF1, and GPHIBP1—were sequenced and APOE R110P emerged as a rare variant with a minor allele frequency below one percent. 

The global frequency of this mutation in the gnomAD variant database is 0.000028, with all seven reported heterozygote carriers having European ancestry (gnomAD v2.1.1 April 2022).

Biological effect

In competitive binding assays, P102R ApoE bound to receptors on human cultured fibroblasts as effectively as control ApoE3. The assays pitted control, labeled low-density lipoprotein (LDL) against P102R isolated from the proband and loaded with the synthetic lipid DMPC (Wardell et al., 1991).

However, the mutation was predicted to be deleterious by several computer algorithms. In an analysis of 31 APOE genetic variants using 16 in silico prediction tools, P102R was classified as “convergent deleterious” (Pires et al., 2017). To qualify for this classification, variants had to receive deleterious predictions from at least three algorithms in each of four categories: sequence homology, supervised-learning, protein-sequence and structure, and consensus-based methods. Consistently, this variant’s PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Apr 2022).

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References

Mutations Citations

1. APOE E21K

Paper Citations

1. Wardell MR, Rall SC Jr, Schaefer EJ, Kane JP, Weisgraber KH. Two apolipoprotein E5 variants illustrate the importance of the position of additional positive charge on receptor-binding activity. J Lipid Res. 1991 Mar;32(3):521-8. PubMed.
2. Abedi AH, Yıldırım Şimşir I, Bayram F, Onay H, Özgür S, Mcintyre A, Toth P, Hegele R. Genetic Variants Associated with Severe Hypertriglyceridemia: LPL, APOC2, APOA5, GPIHBP1, LMF1, and APOE. Turk Kardiyol Dern Ars. 2023 Jan;51(1):10-21. PubMed.
3. Pires AS, Porto WF, Franco OL, Alencar SA. In silico analyses of deleterious missense SNPs of human apolipoprotein E3. Sci Rep. 2017 May 30;7(1):2509. PubMed.

Further Reading

No Available Further Reading