Overview

Position: (GRCh38/hg38):Chr19:44909178 G>T
Position: (GRCh37/hg19):Chr19:45412435 G>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs557715042
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TGG to TGT
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 alters ApoE structure and function substantially (Pires et al., 2017). It was initially sequenced in the 1000 Genomes Project. In the gnomAD variant database, it was found at a frequency of 0.000011, including three heterozygotes, two of Latino/Admixed American ancestry (gnomAD v2.1.1, Oct 2022).

In an analysis of 31 APOE genetic variants using 16 in silico prediction tools, W294C 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.

The W294C substitution results in a non-conservative amino acid change, from hydrophobic to hydrophilic, in an evolutionarily conserved residue. The substitution was predicted to result in loss of hydrogen bonds between ApoE’s N- and C-terminal domains. Consistent with a structural change, computer modeling showed the substitution increasing ApoE’s solvent-accessible area. The authors also speculated the variant might interfere with lipid binding.

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (24.5), consistent with mediating a deleterious effect (CADD v.1.6, Oct 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.

Further Reading

No Available Further Reading