Mature Protein Numbering: E9Afs


Clinical Phenotype: Blood Lipids/Lipoproteins, Kidney Disorder: Nephrotic Syndrome
Reference Assembly: GRCh37/hg19
Position: Chr19:45411053_45411054 AG>-
Transcript: NM_000041; ENSG00000130203
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: Frame Shift
Codon Change: GAG to GCC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 3


This mutation, predicted to eliminate ApoE expression, was identified in heterozygous form in a Spanish family. The proband, a female child, had very high triglyceride levels and elevated ApoB levels in serum, as well as nephrotic syndrome, a kidney disorder characterized by protein in the urine (Corredor-Andrés et al., 2018). Her mother and grandmother had triglyceride levels that were slightly increased. Suspecting a genetic disorder associated with ApoE, hyperlipoproteinemia type III (HLPP3), the authors sequenced the APOE gene. This revealed the girl carried the common APOE alleles APOE3 and R176C (APOE2), as well as a deletion of two nucleotides in exon 3 on the same chromosome as the APOE3 allele. The deletion, together with the APOE2/E3 genotype, was also identified in the proband’s mother, sister, and maternal grandmother. The mutation was absent from the gnomAD variant database.

Of note, two similar pediatric cases, with nephrotic syndrome and very high triglyceride levels, were reported in children homozygous for APOE2, a genotype associated with HLPP3 (Ellis et al., 1995). Also, heterozygote carriers of other mutations coding for truncated ApoE species in the presence of an APOE2 allele (W38Ter, R154Afs, W5Ter, and E114Gfs) have been diagnosed with HLPP3.

Biological Effect

This mutation causes a frameshift resulting in an mRNA coding for a 61-amino acid truncated protein predicted to be degraded by nonsense-mediated mRNA 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
  5. APOE E114Gfs

Paper Citations

  1. . Atypical hyperlipidemia and nephropathy associated with apolipoprotein E homozygosity. J Am Soc Nephrol. 1995 Oct;6(4):1170-7. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

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