APOE E114Gfs

Mature Protein Numbering: E96Gfs

Other Names: ApoE3 Groningen


Clinical Phenotype: Hyperlipoproteinemia Type III
Reference Assembly: GRCh37/hg19
Position: Chr19:45411893 ->G
Transcript: NM_000041; ENSG00000130203
Coding/Non-Coding: Coding
DNA Change: Insertion
Expected RNA Consequence: Insertion
Expected Protein Consequence: Frame Shift
Codon Change: GAG to GAA
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4


This variant, a nucleotide insertion causing a frameshift, was found in a Dutch family in which some carriers suffered from hyperlipoproteinemia type III (HLPP3), also known as familial dysbetalipoproteinemia, a condition characterized by the accumulation of remnants of triglyceride-rich lipoproteins, and early onset atherosclerosis and heart disease (Dijck-Brouwer et al., 2005). The proband developed lipid deposits under his skin starting at age 18, had elevated cholesterol levels at age 35 and was found to have an HLPP3-like lipid and lipoprotein profile at age 49. Due to a genotyping artifact, he was first thought to be homozygous for the R176C (APOE2) allele, a common cause of HLPP3. However, further analyses revealed he was an APOE2/3 heterozygote carrying the E114Gfs mutation on an APOE3 background. The mutation was named APOE3 Groningen, in honor of the city in which it was discovered.

Subsequent genotyping of 19 family members identified five mutation carriers, spanning three generations. Only three carriers were affected, however, having elevated levels of cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C) in serum. Interestingly, all three of these individuals, including the proband, were APOE2 heterozygotes, while the two unaffected carriers were homozygous for the more common APOE3 allele.

The authors concluded that E114Gfs alone, in heterozygote form, is probably insufficient to cause disease. Of note, heterozygote carriers of other mutations also coding for truncated ApoE species, W38Ter, R154Afs, and W5Ter, have been reported to suffer from HLPP3 when carrying an APOE2 allele. Moreover, other genetic or environmental factors may contribute to disease. Indeed, five of the mutation non-carriers in the Dutch family, three APOE3 homozygotes and two APOE2/3 heterozygotes, had elevated lipid indices.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, Apr2022).

Biological Effect

This variant results from the insertion of a guanine in codon 113 or 114 causing a frameshift that results in the replacement of E114 by a glycine and the generation of a premature stop codon at position 164 (Dijck-Brouwer et al., 2005). The predicted consequence is either the expression of a truncated protein and/or the elimination of ApoE synthesis caused by nonsense-mediated RNA decay. Its biological effect is unknown, but together with ApoE2, which binds very poorly to low-density lipoprotein receptors (LDLRs), it is expected to substantially reduce ApoE functionality.

Last Updated: 05 Dec 2022


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Mutations Citations

  1. APOE R176C (ApoE2)
  2. APOE W38Ter
  3. APOE R154Afs
  4. APOE W5Ter

Paper Citations

  1. . Discovery and consequences of apolipoprotein-epsilon(3Groningen): a G-insertion in codon 95/96 that is predicted to cause a premature stop codon. Ann Clin Biochem. 2005 Jul;42(Pt 4):264-8. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Discovery and consequences of apolipoprotein-epsilon(3Groningen): a G-insertion in codon 95/96 that is predicted to cause a premature stop codon. Ann Clin Biochem. 2005 Jul;42(Pt 4):264-8. PubMed.

Other mutations at this position

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