Overview

Position: (GRCh38/hg38):Chr19:44907864 C>T
Position: (GRCh37/hg19):Chr19:45411121 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs11542029
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to TGC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 3

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). Thirteen 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). Moreover, this variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Dec 2022).

Also of note, an artificial substitution at this same site, R50A, substantially reduced binding of ApoE4 to the microglial leukocyte immunoglobulin-like receptor B3 (LilrB3), a receptor that binds to ApoE4 more strongly than to ApoE3 or ApoE2 and activates pro-inflammatory pathways (Zhou et al., 2023). Moreover, a study using FRET and computational simulations to study monomeric ApoE4 predicted interactions between R50, in helix 1 of ApoE's N-terminal domain, and E88, in helix 2. These contacts were predicted to occur when the C-terminal domain is undocked from the N-terminal helix bundle, a form suspected to enable lipid binding (Stuchell-Brereton et al., 2023).

The variant was found in multiple, independent submissions to the refSNP cluster. It is also reported in the gnomAD variant database at a frequency of 0.000012 including three heterozygotes, each of different ancestry: African, East Asian, and European (gnomAD v2.1.1, Dec 2022).

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References

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. Zhou J, Wang Y, Huang G, Yang M, Zhu Y, Jin C, Jing D, Ji K, Shi Y. LilrB3 is a putative cell surface receptor of APOE4. Cell Res. 2023 Feb;33(2):116-130. Epub 2023 Jan 2 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