Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, BP4
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73170995 G>T
Position: (GRCh37/hg19):Chr14:73637703 G>T
dbSNP ID: rs63750601
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTC to TTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was first identified in a Japanese family. The reported pedigree consisted of four affected family members over three generations. All affected individuals had early onset Alzheimer’s disease, with a mean age at onset of 52.5 ± 5.07 years (range: 49 to 60 years). The mutation was found in three affected carriers and three at-risk individuals who had yet to reach the mean age at onset. Moreover, it was absent from several unaffected family members who were past the age of onset, and from 100 non-demented controls (Kamino et al., 1996). It was also absent from the gnomAD variant database (May 2021).

The mutation was also found in two siblings from Malaysia with early onset AD (Giau et al., 2019, Bagyinszky et al., 2021). Both individuals had symptoms that began at age 40. In addition to memory loss, the patients experienced apathy and withdrawal. Both patients had an APOE3/APOE4 genotype. The mutation was absent from the 1000 Genomes database and from 1,1000 unaffected Korean individuals in the KRGDB database.

Neuropathology

Neuropathological data are unavailable, but brain imaging of the Malaysian siblings revealed cerebral volume loss, particularly in the hippocampus, as assessed by MRI (Bagyinszky et al., 2021). One sibling had mild cerebral volume loss, particularly in the temporal and parietal lobes, with robust bilateral loss in the hippocampus and mild loss in the parahippocampal gyri, while the other had mild volume loss only in the right hippocampus.

Biological Effect

In conditioned media from human embryonic kidney cells lacking endogenous PSEN1 and PSEN2 and expressing this variant, the Aβ42/Aβ40 ratio was increased and the Aβ37/Aβ42 ratio was decreased relative to control cells expressing wild-type PSEN1 (Liu et al., 2022; Apr 2022 news). Both ratios were consistent with a pathogenic effect, as revealed by analyses of control and AD human samples, with the Aβ37/Aβ42 ratio distinguishing between the two sets of samples more effectively than Aβ42/Aβ40. In addition, V96F resulted in increased levels of the toxic peptide Aβ43. Elevation of the Aβ42/Aβ40 ratio was also observed in two other cell-based assays (Kamino et al., 1996; Brunkan et al., 2005), and V96F's endopeptidase activity was found to be disrupted (Brunkan et al., 2005).

Although an in vitro study reported an abrogation of Aβ40 production and a drastic reduction in Aβ42 production (Sun et al., 2017), the reliability of this assay has been called into question given that nearly half of 138 mutant recombinant PSEN1 proteins tested produced less than 10 percent of the Aβ40 and Aβ42 produced by the wildtype protein (Liu et al., 2021).

Several in silico algorithms predicted this variant is damaging (Xiao et al., 2021) and 3D modeling suggested alterations in intramolecular interactions that could affect protein function (Bagyinszky et al., 2021). However, at least one algorithm failed to predict a damaging effect (Giau et al., 2019), and the CADD-PHRED tool, which integrates diverse information, gave it a low deleteriousness score below 20 (CADD v.1.6, Sep 2021).

Pathogenicity

Alzheimer's Disease : Pathogenic

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.

PP1-S

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. V96F: At least one family with >=3 affected carriers and >=1 unaffected noncarriers.

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.

BP4-P

Multiple lines of computational evidence suggest no impact on 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 less than 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 Feb 2024

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References

News Citations

Paper Citations

Kamino K, Sato S, Sakaki Y, Yoshiiwa A, Nishiwaki Y, Takeda M, Tanabe H, Nishimura T, Ii K, St George-Hyslop PH, Miki T, Ogihara T. Three different mutations of presenilin 1 gene in early-onset Alzheimer's disease families. Neurosci Lett. 1996 Apr 26;208(3):195-8. PubMed.
Giau VV, Bagyinszky E, Youn YC, An SS, Kim S. APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease. Int J Mol Sci. 2019 Sep 25;20(19) PubMed.
Bagyinszky E, Ch'ng GS, Chan MY, An SS, Kim S. A Pathogenic Presenilin-1 Val96Phe Mutation from a Malaysian Family. Brain Sci. 2021 Oct 8;11(10) PubMed.
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.
Brunkan AL, Martinez M, Wang J, Walker ES, Beher D, Shearman MS, Goate AM. Two domains within the first putative transmembrane domain of presenilin 1 differentially influence presenilinase and gamma-secretase activity. J Neurochem. 2005 Sep;94(5):1315-28. 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.
Liu L, Lauro BM, Wolfe MS, Selkoe DJ. Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 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 V96F

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