Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198049 G>T
Position: (GRCh37/hg19):Chr14:73664757 G>T
dbSNP ID: rs63751102
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TGT to TTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

The mutation was found in a study of British AD patients with a family history of AD with at least one affected first-degree relative, and an age of onset of less than 61 years (Janssen et al., 2003). The age of onset of the proband was 58 years. Three members of the individual’s family, spanning two generations, were diagnosed with AD, with a mean age of onset of 58 years. DNA was unavailable from the affected relatives, however, so co-segregation of the mutation and disease could not be demonstrated. The mutation was absent from 100 healthy, unrelated white control patients.

The mutation was subsequently reported in two French families suffering from AD with a range of disease onset between 48 and 65 years of age (Lanoiselee et al., 2017), and in five Belgian AD patients, three with onset before age 66 (Perrone et al., 2020). Except for one early onset carrier who had an APOE3/4 genotype, the other four Belgian carriers were homozygous for APOE3.

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

Neuropathology
Neuropathological data are unavailable. However, in three of four cases, cerebrospinal fluid biomarkers were consistent with AD (Lanoiselee et al., 2017; Perrone et al., 2020). Two carriers whose Aβ profiles were analyzed in greater detail revealed potential differences between early and late onset disease (Perrone et al., 2020). In the late-onset case, Aβ42 and Aβ43 levels were decreased, while Aβ40 levels were increased, resulting in a decreased Aβ42/Aβ40 ratio characteristic of AD. This individual also had increased levels of sAPPα, and sAPPβ, as well as increased levels of tau and phospho-tau. In contrast, a carrier with early onset AD, had increased levels of Aβ40, Aβ42, and Aβ43, decreased levels of sAPPα, and sAPPβ, and normal levels of tau and phospho-tau. The Aβ42/Aβ40 ratio in this case was borderline. Both carriers were homozygous for APOE3.

Biological Effects
A cell-based assay showed decreased levels of the APP intracellular domain (AICD), which reflects total Aβ production, as well as reductions in Aβ38, Aβ40, and Aβ42 production. However, the Aβ42/Aβ40 ratio was increased, as was production of toxic Aβ43 (Kakuda et al., 2021). The latter increase may be due to a switch in the stepwise processing pathway that leads to Aβ43 production. Interestingly, the magnitude of this alteration caused by different familial AD mutations correlated with disease age at onset.

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue may help stabilize the structural re-arrangement of PSEN1 upon APP binding (Zhou et al., 2019; Jan 2019 news).

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). These authors classified the variant as likely pathogenic using the ACMG-AMP guidelines (Richards et al., 2015).

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. C263F: Although the variant decreased total Aβ peptide, Aβ42, and Aβ40 production in cells, it increased Aβ43 and the Aβ42/Aβ40 ratio.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. C263F: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. C263F: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

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: 04 Mar 2022

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References

News Citations

Paper Citations

Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, Houlden H, Rossor MN, Collinge J. Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
Lanoiselée HM, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, Richard AC, Pasquier F, Rollin-Sillaire A, Martinaud O, Quillard-Muraine M, de la Sayette V, Boutoleau-Bretonniere C, Etcharry-Bouyx F, Chauviré V, Sarazin M, le Ber I, Epelbaum S, Jonveaux T, Rouaud O, Ceccaldi M, Félician O, Godefroy O, Formaglio M, Croisile B, Auriacombe S, Chamard L, Vincent JL, Sauvée M, Marelli-Tosi C, Gabelle A, Ozsancak C, Pariente J, Paquet C, Hannequin D, Campion D, collaborators of the CNR-MAJ project. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
Perrone F, Bjerke M, Hens E, Sieben A, Timmers M, De Roeck A, Vandenberghe R, Sleegers K, Martin JJ, De Deyn PP, Engelborghs S, van der Zee J, Van Broeckhoven C, Cacace R, BELNEU Consortium. Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108. PubMed.
Kakuda N, Takami M, Okochi M, Kasuga K, Ihara Y, Ikeuchi T. Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. PubMed.
Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 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.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

Mutations

PSEN1 C263F

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