Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PP2, PP3, BS3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73217210 A>G
Position: (GRCh37/hg19):Chr14:73683918 A>G
dbSNP ID: rs63751254
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAC to AGC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation was found in a Japanese woman with early onset AD (Yasuda et al., 2000). The woman developed memory impairment at age 48, and progressed rapidly to dementia with spasticity within a year, eventually becoming motionless and mute and dying at age 53. She had no known family history of dementia. The mutation was absent from 100 controls and 100 cases of sporadic AD, as well as from the gnomAD variant database (gnomAD v2.1.1, August 2021).

Neuropathology
Neuropathology of this single case was consistent with AD, with minimal cerebral amyloid angiopathy.

Biological Effect
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed decreased Aβ40 and Aβ42 production, and a decreased Aβ42/Aβ40 ratio (Sun et al., 2017). In silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Xiao et al., 2021), but the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).

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.

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.

BS3-S

Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing. N405S: The variant reduced Aβ42 and Aβ40 production in vitro and decreased the Aβ42/Aβ40 ratio, effects predicted to be benign or protective.

	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

Yasuda M, Maeda S, Kawamata T, Tamaoka A, Yamamoto Y, Kuroda S, Maeda K, Tanaka C. Novel presenilin-1 mutation with widespread cortical amyloid deposition but limited cerebral amyloid angiopathy. J Neurol Neurosurg Psychiatry. 2000 Feb;68(2):220-3. PubMed.
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.
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.

Mutations

PSEN1 N405S

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