Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173630 A>T
Position: (GRCh37/hg19):Chr14:73640338 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAT to TAT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This variant was identified in a woman who developed symptoms at age 32, starting with forgetfulness and confusion. By age 39 she had spasticity in both arms. She later developed other motor symptoms including a gait abnormality, described as “wide based” and “scissoring.” She enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study and participated in neuropsychological testing and quantitative brain imaging. Her father had died at age 48 after being in a severe stage of dementia for three years. His cognitive symptoms began rapidly at age 42 and were accompanied by visual and auditory hallucinations. His clinical diagnosis of AD was confirmed by autopsy. He had a seizure disorder as a child. There were no other known cases of dementia in the family (Natelson Love et al., 2016).

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

Neuropathology

The proband’s MRI showed decreased volume in many regions, including the bilateral precuneus, hippocampus, entorhinal cortex, parahippocampal cortex, lateral occipital cortex, and amygdala, among others (Natelson Love et al., 2016). FDG-PET showed decreased metabolism in many regions, including the bilateral precuneus, posterior cingulate, and lateral orbitofrontal cortices. The left hippocampus had striking hypermetabolism. PiB-PET imaging showed amyloid in the brainstem, striatum, temporal lobes, parietal lobes, and occipital lobes, among other areas. Video-EEG telemetry monitoring showed epileptiform activity in both frontal lobes.

The autopsy report of the proband’s father confirmed his AD diagnosis. Findings included striking cerebral atrophy, especially in the frontal and temporal lobes, the hippocampus, and the amygdala, whereas the basal ganglia, subthalamic nucleus, red nucleus, and substantia nigra were relatively spared. White matter was moderately reduced. Neuritic plaques ranged from “moderate” to “frequent” resulting in a CERAD designation of C. There were numerous neurofibrillary tangles in the hippocampal formation and the neocortex, resulting in a Braak and Braak stage of V/VI. No Lewy bodies were observed.

Biological Effect

When expressed in 7PA2 Chinese hamster ovarian cells stably overexpressing human APP, the N135Y mutation in PSEN1 produced less secreted Aβ40 and had a higher Aβ42/Aβ40 ratio than cells expressing wild-type presenilin-1 (Natelson Love et al., 2016). Moreover, the Aβ42/Aβ40 ratio was also elevated in transfected human embryonic kidney cells (N135Y: 0.40 vs WT:0.15) and the Aβ37/Aβ42 ratio was decreased (N135Y: 0.13 vs WT:0.44), as reported in a preprint (Liu et al., 2024). Notably, the latter ratio has been reported to outperform the former as an indicator of AD pathogenicity for PSEN1 variants (Liu et al., 2022, Apr 2022 news). Also of note, the PSEN2 homolog of N135Y, N141Y, similarly altered the Aβ42/Aβ40 and Aβ37/Aβ42 ratios and was classified as pathogenic (Liu et al., 2024).

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 : 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.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

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.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

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: 15 Aug 2024

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References

News Citations

Mutations Citations

Paper Citations

Natelson Love M, Clark DG, Cochran JN, Den Beste KA, Geldmacher DS, Benzinger TL, Gordon BA, Morris JC, Bateman RJ, Roberson ED. Clinical, imaging, pathological, and biochemical characterization of a novel presenilin 1 mutation (N135Y) causing Alzheimer's disease. Neurobiol Aging. 2017 Jan;49:216.e7-216.e13. Epub 2016 Oct 3 PubMed.
Liu L, Schultz S, Saba A, Yang H-S, Li A, Selkoe D, Chhatwal J. The pathogenicity of PSEN2 variants is tied to Aβ production and homology to PSEN1. 2024 Jun 28 10.1101/2024.06.22.600217 (version 1) bioRxiv.
Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; 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 N135Y

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