Overview

Clinical Phenotype: Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type III
Reference Assembly: GRCh37/hg19
Position: Chr19:45411087 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Nonsense
Codon Change: TGG to TGA
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 3

Findings

This variant was identified in a German family in which the proband suffered from hyperlipoproteinemia type III (HLPP3), also known as familial dysbetalipoproteinemia, but the variant did not segregate with the condition (Feussner et al., 1998). The proband, a 52-year-old woman, was part of a cohort of 107 individuals diagnosed with HLPP3 which is characterized by the accumulation of remnants of triglyceride-rich lipoproteins, and early onset atherosclerosis and heart disease. Analysis of the family revealed three additional mutation carriers, two who had normal blood lipid profiles and one with moderate hyperlipidemia. Moreover, three non-carriers were hyperlipidemic.

Interestingly, the two mutation carriers who had abnormal lipid profiles, including a high ratio of very low-density lipoprotein cholesterol (VLDL-C) to triglycerides characteristic of HLPP3, also carried the R176C (APOE2) allele which, in homozygous form, is a major cause of HLPP3. The other two W38Ter mutation carriers, whose lipid profiles were normal, had an APOE3/3 genotype. The authors concluded that this mutation alone is insufficient to cause disease. Of note, heterozygote carriers of other mutations also coding for truncated ApoE species, W5Ter, R154Afs, and E114Gfs, suffered from HLPP3 when carrying APOE2, but not APOE3 or APOE4, on the other chromosome.

This variant was absent from the gnomAD variant database (v2.1.1 July 2021).

Biological Effect

W38Ter, which introduces a stop codon close to the N-terminus of ApoE, is predicted to produce a truncated protein and/or low levels of ApoE due to nonsense-mediated decay of its encoding mRNA. However, measurements of ApoE levels in serum failed to show a consistent effect. While two unaffected mutation carriers had low ApoE levels, one of the affected carriers had normal levels and, surprisingly, the affected proband’s levels were abnormally high.

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

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References

Mutations Citations

1. APOE R176C (ApoE2)
2. APOE W5Ter
3. APOE R154fs
4. APOE E114fs

Paper Citations

1. Feussner G, Feussner V, Hoffmann MM, Lohrmann J, Wieland H, März W. Molecular basis of type III hyperlipoproteinemia in Germany. Hum Mutat. 1998;11(6):417-23. PubMed.

Further Reading

No Available Further Reading