Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198115 C>T
Position: (GRCh37/hg19):Chr14:73664823 C>T
dbSNP ID: rs63751139
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCT to GTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was originally found in a Japanese individual who presented with disorientation at age 47 and subsequently developed rapidly progressing global cognitive impairment with apraxia and memory loss over the next two years (Ikeda et al., 1996). The proband’s mother also developed progressive dementia at age 55. No family members in addition to the proband were available to confirm co-segregation of the mutation with disease. However, the mutation was absent from 140 controls of Japanese origin, 200 white controls, and 100 subjects of different ethnicities suffering from sporadic AD with age of onset greater than 65 years. 

The mutation was also identified in two members of a second Japanese family with a mean AD age of onset of 50 years (Aoki et al., 1997). The mutation was absent from one unaffected family member and 70 unrelated Japanese controls. Both mutation carriers, a parent and child, first developed memory impairment followed by personality changes. 

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology
Neuropathology data are unavailable, but MRI scans from two patients revealed atrophy of temporo-parietal cortical areas, and tau levels were elevated in the CSF of one patient (Ikeda et al., 1996; Aoki et al., 1997). Hippocampal atrophy was also reported, as well as abnormalities in the deep white matter of the parieto-occipital lobes. SPECT showed hypoperfusion in parietal and occipital areas. Levels of Aβ40 and Aβ42 in the CSF of one patient were similar to those of healthy controls (Aoki et al., 1997).

Biological Effect
In HEK293 cells co-expressing Swedish mutant APP with the A285V mutant, the fraction of total Aβ production contributed by Aβ42 was approximately fourfold greater than in cells transfected with wild-type PSEN1. Consistently, Aβ38 and Aβ40 contributions were reduced (Page et al., 2008). However, an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate indicated A285V modestly decreases both Aβ40 and Aβ42 production, resulting in an Aβ42/Aβ40 ratio similar to that generated by wild-type PSEN1 (Sun et al., 2017). 

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Likely Pathogenic

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. Ikeda M, Sharma V, Sumi SM, Rogaeva EA, Poorkaj P, Sherrington R, Nee L, Tsuda T, Oda N, Watanabe M, Aoki M, Shoji M, Abe K, Itoyama Y, Hirai S, Schellenberg GD, Bird TD, St George-Hyslop PH. The clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients. Ann Neurol. 1996 Dec;40(6):912-7. PubMed.
2. Aoki M, Abe K, Oda N, Ikeda M, Tsuda T, Kanai M, Shoji M, St George-Hyslop PH, Itoyama Y. A presenilin-1 mutation in a Japanese family with Alzheimer's disease and distinctive abnormalities on cranial MRI. Neurology. 1997 Apr;48(4):1118-20. PubMed.
3. Page RM, Baumann K, Tomioka M, Pérez-Revuelta BI, Fukumori A, Jacobsen H, Flohr A, Luebbers T, Ozmen L, Steiner H, Haass C. Generation of Abeta38 and Abeta42 is independently and differentially affected by familial Alzheimer disease-associated presenilin mutations and gamma-secretase modulation. J Biol Chem. 2008 Jan 11;283(2):677-83. PubMed.
4. Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
5. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

1. gnomAD v2.1.1

Further Reading