Overview

Position: (GRCh38/hg38):Chr19:44908751 G>A
Position: (GRCh37/hg19):Chr19:45412008 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs28931578
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGG to CAG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was identified in five Dutch individuals (de Knijff et al., 1994, unpublished findings). Two probands carrying the mutation and the R176C (APOE2) allele were reported as having no metabolic abnormalities.

The variant is present in the gnomAD variant database at a frequency of 0.000032 with an allele count of 6 (gnomAD v2.1.1, July 2021). All counts were reported in European (non-Finnish) individuals. The variant is also found in the non-neuro subdivision of gnomAD at a frequency of 0.000037 with an allele count of 5.

Biological effect

The biological effect of this variant is unknown. The authors noted, however, that although it removes one of the positive charges from the ApoE receptor binding domain, it may not disrupt receptor binding substantially (de Knijff et al., 1994). Unlike most positively charged amino acids in this region which are predicted to face outward, potentially facilitating receptor interactions, R152 is predicted to face inward. The variant may affect ApoE conformation, however. A study using FRET and computational simulations to study monomeric ApoE4, predicted long-range interactions between R152 and E63 (Stuchell-Brereton et al., 2023). This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, May 2022).

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References

Mutations Citations

1. APOE R176C (ApoE2)

Paper Citations

1. de Knijff P, van den Maagdenberg AM, Frants RR, Havekes LM. Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels. Hum Mutat. 1994;4(3):178-94. PubMed.
2. Stuchell-Brereton MD, Zimmerman MI, Miller JJ, Mallimadugula UL, Incicco JJ, Roy D, Smith LG, Cubuk J, Baban B, DeKoster GT, Frieden C, Bowman GR, Soranno A. Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms. Proc Natl Acad Sci U S A. 2023 Feb 14;120(7):e2215371120. Epub 2023 Feb 7 PubMed.

Further Reading

No Available Further Reading