Mutations

APP E665D

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PP2, BS2, BS3, BP4
Clinical Phenotype: None
Position: (GRCh38/hg38):Chr21:25897642 G>C
Position: (GRCh37/hg19):Chr21:27269954 G>C
dbSNP ID: rs63750363
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAG to GAC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 16

Findings

This variant was detected in a person with late-onset Alzheimer's disease (Peacock et al., 1994). However, it did not segregate with disease as it was also found in a cognitively healthy relative (who was older than 65).

The variant was found in the gnomAD variant database at a frequency of 0.00001193, with an allele count of three (v.2.1.1, Oct 2021). 

Neuropathology

Not applicable.

Biological Effect

Mouse neuroblastoma cells expressing this variant secreted similar amounts of Aβ42 and Aβ40 compared with cells expressing wild-type APP, and the resutling Aβ42/Aβ40 ratio was also similar to controls (Hsu et al., 2020). Moreover, the variant's PHRED-scaled CADD score, which integrates diverse information in silico did not reach 20, a threshold often used to predict deleteriousness (CADD v.1.6, Oct 2021).

Pathogenicity

Alzheimer's Disease : Benign

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

BS2-S

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.

BS3-S

Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing.

BP4-P

Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is less than 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 16 Mar 2022

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References

Paper Citations

  1. Peacock ML Jr, Murman DL, Sima AA, Warren JT, Roses AD, Fink JK. Novel amyloid precursor protein gene mutation (codon 665Asp) in a patient with late-onset Alzheimer's disease. Ann Neurol. 1994 Apr;35(4):432-8. PubMed.
  2. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Peacock ML Jr, Murman DL, Sima AA, Warren JT, Roses AD, Fink JK. Novel amyloid precursor protein gene mutation (codon 665Asp) in a patient with late-onset Alzheimer's disease. Ann Neurol. 1994 Apr;35(4):432-8. PubMed.

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