Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25897592 A>T
Position: (GRCh37/hg19):Chr21:27269904 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAA to GTA
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 16

Findings

This variant was identified by whole-exome sequencing in a Han Chinese family spanning two generations (Zhaoxia et al., 2023). The proband was a 65-year-old woman whose symptoms, including memory loss and slowed reaction time, emerged at age 61. She was diagnosed with Alzheimer’s disease (AD). Two of her aunts and six of their children had similar symptoms. The proband’s father, however, was diagnosed with Parkinson’s disease. The report states that the variant co-segregated with disease—it was carried by affected, but not unaffected, family members, but specific data were not provided.
This variant was absent from the gnomAD variant database (v2.1.1, Aug 2023).

Neuropathology
Neuropathological data are unavailable, but a brain MRI scan of the proband revealed multiple cerebral infarctions and paraventricular leukoaraiosis (Zhaoxia et al., 2023). Susceptibility Weighted Imaging showed several microbleeds in both cerebral hemispheres and the cerebellum. The same imaging technique was reported as revealing amyloidosis.

Biological Effect
The biological effect of this variant is unknown, but the in silico algorithm Mutation Taster predicted it is damaging (Zhaoxia et al., 2023). Moreover, this variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (33), suggesting a deleterious effect (CADD v.1.6, Aug 2023).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

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

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PP1-P

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. E682V: Although the publication states this variant co-segregated with disease, no data were provided.

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.

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.

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

Mutations

APP E682V

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Overview

Findings

Pathogenicity

Alzheimer's Disease : Not Classified*

PM1-M

PM2-M

PP1-P

PP2-P

PP3-P

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References

Paper Citations

Further Reading

Protein Diagram

Primary Papers

Other mutations at this position