Mutations

APP E380K

Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PP3, BS1
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25982430 G>A
Position: (GRCh37/hg19):Chr21:27354743 G>A
dbSNP ID: rs755703063
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAG to AAG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 9

Findings

This variant was identified in a targeted sequencing study of Saudi Arabian sporadic and familial Alzheimer’s cases (El Bitar et al., 2019). The carrier—heterozygous for this variant—was classified as a sporadic late-onset AD case. Clinical features included impairments in learning and recalling new information, and imaging revealed brain atrophy.

The E380K variant was absent from the 1000 Genomes database. It was found with an allele frequency of 1.26 X 10-3 in 2,500 ethnically matched controls from the Saudi Human Genome Program Database (El Bitar et al., 2019). One African and five non-Finnish European heterozygotes were found in gnomAD (v2.1.1., searched 2020-10-14).

Biological Effect

The effect of the glutamate-to-lysine substitution has not been tested directly. However, the variant is predicted to be probably damaging by PolyPhen-2, damaging by SIFT, and neutral by PROVEAN, and it is classified as disease-causing by Mutation Taster. The PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021).

Pathogenicity

Alzheimer's Disease : Uncertain Significance

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

PP3-P

Multiple lines of computational evidence support a deleterious effect on the 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 greater than or equal to 20.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  E380K: Most carriers are of non-Finnish European descent.

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

Last Updated: 22 Feb 2022

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References

Paper Citations

  1. El Bitar F, Qadi N, Al Rajeh S, Majrashi A, Abdulaziz S, Majrashi N, Al Inizi M, Taher A, Al Tassan N. Genetic Study of Alzheimer's Disease in Saudi Population. J Alzheimers Dis. 2019;67(1):231-242. PubMed.

External Citations

  1. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. El Bitar F, Qadi N, Al Rajeh S, Majrashi A, Abdulaziz S, Majrashi N, Al Inizi M, Taher A, Al Tassan N. Genetic Study of Alzheimer's Disease in Saudi Population. J Alzheimers Dis. 2019;67(1):231-242. PubMed.

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