Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73171004 A>G
Position: (GRCh37/hg19):Chr14:73637712 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACC to GCC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was identified in a Japanese man with early onset Alzheimer’s disease. Signs of cognitive impairment began at age 43 and he met NINCDS-ADRDA criteria for AD (Ikeda et al., 2013). APOE genotyping revealed he carried APOE3 and APOE4 alleles. This variant was absent from the EVS and ExAC variant databases (Hsu et al., 2020).

Neuropathology

Neuropathological data are unavailable, but seven years after dementia onset, MRI showed atrophy of the parietal and frontal lobes.

Biological Effect

Three different assays yielded mixed results, but all suggested some deleterious effects, including increased Aβ42/Aβ40 and decreased Aβ37/Aβ42 ratios. An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed reduced production of Aβ42, and particularly Aβ40, resulting in an approximately 7-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). An assessment of secreted Aβ40 and Aβ42 in N2 cells expressing the PSEN1 T99A on a PSEN1/PSEN2 null background also revealed an increased Aβ42/Aβ40 ratio but, in this case, secretion of Aβ42 roughly doubled, while that of Aβ40 was similar to controls (Hsu et al., 2020). Lastly, in conditioned media of human embryonic kidney cells lacking endogenous PSEN1 and PSEN2 and expressing this variant, the Aβ42/Aβ40 was similar to that measured in the media of control cells, but the Aβ37/Aβ42 ratio was decreased, suggesting a damaging effect (Liu et al., 2022, Apr 2022 news). Of note, the Aβ37/Aβ42 ratio outperformed Aβ42/Aβ40 at distinguishing control versus AD samples.

Position 99 is conserved between PSEN1 and PSEN2. Although some in silico algorithms to predict the effects of this variant on protein function (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, REVEL, and Reve in the VarCards database) yielded conflicting results (Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021). Hsu et al. classified it as probably pathogenic (Hsu et al., 2020).

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-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. T99A: Three different assays yielded mixed results, but all suggested deleterious effects, including increased Aβ42/Aβ40 and decreased Aβ37/Aβ42 ratios.

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.

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: 11 Apr 2022

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References

News Citations

Paper Citations

Ikeda M, Yonemura K, Kakuda S, Tashiro Y, Fujita Y, Takai E, Hashimoto Y, Makioka K, Furuta N, Ishiguro K, Maruki R, Yoshida J, Miyaguchi O, Tsukie T, Kuwano R, Yamazaki T, Yamaguchi H, Amari M, Takatama M, Harigaya Y, Okamoto K. Cerebrospinal fluid levels of phosphorylated tau and Aβ1-38/Aβ1-40/Aβ1-42 in Alzheimer's disease with PS1 mutations. Amyloid. 2013 Jun;20(2):107-12. PubMed.
Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 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, 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 T99A

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