Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227073340 C>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACC to AGC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6

Findings

This variant was found in a study that screened the APP, PSEN1, and PSEN2 genes in 1,431 Alzheimer’s disease (AD) patients from the Belgian neurology consortium BELNEU (Perrone et al., 2020). The authors used a targeted re-sequencing gene panel and selected non-synonymous variants with a minor allele frequency of less than 1 percent.

The carrier of this variant suffered from early onset Alzheimer’s disease and was homozygous for the APOE3 allele. The variant was absent from the gnomAD variant database.

Neuropathology
Neuropathological data are unavailable, but the carrier had reduced levels of Aβ43 and Aβ42 in cerebrospinal fluid (CSF), similar to those observed in carriers of known pathogenic mutations. In addition, Aβ40, sAPPα, and sAPPβ were also reduced. Tau and phospho-tau levels, however, were within the normal range. 

Biological Effect
The biological effects of this variant are unknown, but its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 2021). Perrone and colleagues suggested classifying this variant as "likely pathogenic" based on their findings of altered Aβ peptides in CSF, particularly Aβ43 (Perrone et al., 2020). However, functional assays to directly determine the variant's biological effects are lacking.

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.

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References

Paper Citations

1. Perrone F, Bjerke M, Hens E, Sieben A, Timmers M, De Roeck A, Vandenberghe R, Sleegers K, Martin JJ, De Deyn PP, Engelborghs S, van der Zee J, Van Broeckhoven C, Cacace R, BELNEU Consortium. Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108. PubMed.

Further Reading

No Available Further Reading