Mutations

APP N698D

Other Names: Ghent mutation, p.[Asn698Asp]

Overview

Pathogenicity: Cerebral Amyloid Angiopathy : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Stroke
Position: (GRCh38/hg38):Chr21:25891842 A>G
Position: (GRCh37/hg19):Chr21:27264154 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAC to GAC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This variant was identified in a 75-year-old Belgian woman with recurrent stroke and diffuse leukoencephalopathy consistent with cerebral amyloid angiopathy and small vessel disease (Schuermans et al., 2023). The variant was found by exome sequencing and large gene panel analysis covering 725 genes of 1,411 patients with molecularly unexplained neurologic phenotypes at the Ghent University Hospital.

The proband had an affected older brother who was not genotyped. He had rapid cognitive decline with recurrent stroke, periventricular leukodystrophy, and multiple lacunar infarcts.

The variant was absent from population database gnomAD.

Neuropathology
Neuropathological data are unavailable, but brain MRI of the proband indicated widespread microangiopathy with diffuse confluent leukoencephalopathy, lacunar infarctions, and involvement of basal ganglia, pons, and right cerebral peduncle as assessed by FLAIR imaging, as well as several cerebral microbleeds as assessed by SWI (Schuermans et al., 2023).

Moreover, analysis of the proband’s cerebrospinal fluid showed Aβ42 within the normal range, with a slight elevation of total tau.

Biological Effect
The biological effect of this variant is unknown. Although N698 is only moderately conserved, it is located in a highly conserved region, close to a few pathogenic variants which attenuate α-secretase cleavage (Schuermans et al., 2023). This variant's PHRED-scaled CADD score was above 20 (25.6), suggesting a damaging effect.

Pathogenicity

Cerebral Amyloid Angiopathy : 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-P

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. N698D: Located at the edge of a mutational hotspot.

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.

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)

Last Updated: 28 Aug 2023

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References

Paper Citations

  1. Schuermans N, Verdin H, Ghijsels J, Hellemans M, Debackere E, Bogaert E, Symoens S, Naesens L, Lecomte E, Crosiers D, Bergmans B, Verhoeven K, Poppe B, Laureys G, Herdewyn S, Van Langenhove T, Santens P, De Bleecker JL, Hemelsoet D, Dermaut B, for Program for Undiagnosed Rare Diseases (UD-PrOZA). Exome Sequencing and Multigene Panel Testing in 1,411 Patients With Adult-Onset Neurologic Disorders. Neurol Genet. 2023 Jun;9(3):e200071. Epub 2023 Apr 26 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Schuermans N, Verdin H, Ghijsels J, Hellemans M, Debackere E, Bogaert E, Symoens S, Naesens L, Lecomte E, Crosiers D, Bergmans B, Verhoeven K, Poppe B, Laureys G, Herdewyn S, Van Langenhove T, Santens P, De Bleecker JL, Hemelsoet D, Dermaut B, for Program for Undiagnosed Rare Diseases (UD-PrOZA). Exome Sequencing and Multigene Panel Testing in 1,411 Patients With Adult-Onset Neurologic Disorders. Neurol Genet. 2023 Jun;9(3):e200071. Epub 2023 Apr 26 PubMed.

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