Overview

Position: (GRCh38/hg38):Chr19:44908750 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs531939919
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGG to TGG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant has not been associated with any disease or condition, but computer modeling suggests it is damaging. It was reported in a study that analyzed missense single nucleotide polymporhisms (SNPs) in APOE retrieved from the NCBI database dbSNP (Pires et al., 2017). Fourteen of 16 in silico prediction tools, including algorithms in each of four categories—sequence homology, supervised-learning, protein-sequence and structure, and consensus-based methods—predicted the variant was damaging (see supplemental table 2 in Pires et al., 2017). Moreover, this variant removes one of the positive charges from the ApoE receptor binding domain and its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Dec 2022).

However, the effects on receptor binding of another variant at this site which also removes a positive charge, R152Q, were called into question (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. R152W may affect ApoE conformation, however. A  study using FRET and computational simulations to study monomeric ApoE4, predicted long-range interactions between R152 and E63 in all ApoE4 configurations, including open, extended, and closed (Stuchell-Brereton et al., 2023).

The variant was found in the 1000 Genomes Project. It was also reported in the gnomAD variant database at a frequency of 0.000025, including two Latino/Admixed American and two European heterozygotes (gnomAD v2.1.1, Dec 2022).

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References

Mutations Citations

1. APOE R152Q

Paper Citations

1. 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.
2. 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.
3. 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