Mutations
APP E665D
Quick Links
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
References
Paper Citations
- 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.
- 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
- 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.
Alzpedia
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