Mutations

APOE R292H

Mature Protein Numbering: R274H

Overview

Clinical Phenotype: Blood Lipids/Lipoproteins
Position: (GRCh38/hg38):Chr19:44909171 G>A
Position: (GRCh37/hg19):Chr19:45412428 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs121918398
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to CAC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This rare variant was found in an individual from a randomly collected population of healthy 35-year-old Dutch men (van den Maagdenberg et al., 1993, Smit et al., 1988). At age 40, the proband was described as being normolipidemic and having a normal lipoprotein profile in blood, although his total cholesterol levels (5.7 mmol/L) were slightly above the normal range (van den Maagdenberg et al., 1993).

Isoelectric focusing of his ApoE protein resulted in two bands: one corresponding to the common ApoE3 allele and a second migrating to a slightly more cathodic position than C130R (ApoE4). DNA sequencing revealed a wildtype APOE3 allele and an APOE4 allele with an additional nucleotide change resulting in the R292H variant. The mutation was also found in the proband’s 76-year-old mother and three of his four sisters. Except for one of the sisters, all carriers had moderately elevated cholesterol. Of note, the proband’s father, a non-carrier, had higher levels of cholesterol than any of the other members examined, as well as elevated triglycerides. All carriers had normal triglyceride levels. 

A single European (non-Finnish) heterozygote was reported in the gnomAD variant database (v2.1.1, Oct 2022). The variant’s global frequency was 0.0000045.

Biological Effect

The biological effect of this variant is unknown, but its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (25.3) suggesting a deleterious effect (CADD v.1.6, Oct 2022).

Last Updated: 05 Dec 2022

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References

Paper Citations

  1. . Characterization of five new mutants in the carboxyl-terminal domain of human apolipoprotein E: no cosegregation with severe hyperlipidemia. Am J Hum Genet. 1993 May;52(5):937-46. PubMed.
  2. . Apolipoprotein E polymorphism in The Netherlands and its effect on plasma lipid and apolipoprotein levels. Hum Genet. 1988 Nov;80(3):287-92. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Characterization of five new mutants in the carboxyl-terminal domain of human apolipoprotein E: no cosegregation with severe hyperlipidemia. Am J Hum Genet. 1993 May;52(5):937-46. PubMed.

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