Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198060 C>T
Position: (GRCh37/hg19):Chr14:73664768 C>T
dbSNP ID: rs63751229
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCA to TCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in a family from the United Kingdom referred to as F196 (Clark et al., 1995; Hutton et al., 1996). In three generations, five family members were affected by Alzheimer’s disease and had postmortem confirmation of the diagnosis. It is unclear how many family members were genotyped, but the P267S mutation was said to segregate with disease in this family, and the authors noted it was not observed in unaffected, elderly family members or controls. Onset was very early in this family, ranging from 32 to 38 years of age.

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

Neuropathology

Five affected family members had neuropathology consistent with Alzheimer's disease (Clark et al., 1995).

Biological Effect

Experiments in cells and in vitro indicate this mutation alters APP processing, although its effects remain uncertain. In mouse embryonic fibroblasts lacking PSEN1 and PSEN2, expression of the P267S mutant resulted in reduced Aβ42 and Aβ40 production with no change in the Aβ42/Aβ40 ratio compared with cells expressing wild-type PSEN1 (Ben-Gedalya et al., 2015). A study using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate, however, indicated the mutant reduced Aβ40 production and sightly increased Aβ42 production, resulting in an approximately five-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). Interestingly, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicated this residue may help stabilize the structural re-arrangement of PSEN1 upon APP binding (Zhou et al., 2019; Jan 2019 news).

The mutation has also been reported to abolish a recognition site for cyclophilin B, a chaperone protein in the endoplasmic reticulum that assists in PSEN1 folding and maturation, and in vitro, the mutant undergoes enhanced proteolytic degradation (Ben-Gedalya et al., 2015). Moreover, P267S is one of several mutations in PSEN1 found to potentiate cell-cycle arrest when mutant protein is overexpressed in HeLa cells (Janicki et al., 2000).

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-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. P267S: Functional observations are mixed, but most suggest damaging effect.

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. P267S: 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.

PP1-P

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.

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: 29 Nov 2022

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References

News Citations

Paper Citations

Alzheimer's Disease Collaborative Group. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet. 1995 Oct;11(2):219-22. PubMed.
Hutton M, Busfield F, Wragg M, Crook R, Perez-Tur J, Clark RF, Prihar G, Talbot C, Phillips H, Wright K, Baker M, Lendon C, Duff K, Martinez A, Houlden H, Nichols A, Karran E, Roberts G, Roques P, Rossor M, Venter JC, Adams MD, Cline RT, Phillips CA, Goate A. Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. Neuroreport. 1996 Feb 29;7(3):801-5. PubMed.
Ben-Gedalya T, Moll L, Bejerano-Sagie M, Frere S, Cabral WA, Friedmann-Morvinski D, Slutsky I, Burstyn-Cohen T, Marini JC, Cohen E. Alzheimer's disease-causing proline substitutions lead to presenilin 1 aggregation and malfunction. EMBO J. 2015 Nov 12;34(22):2820-39. Epub 2015 Oct 5 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.
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.
Janicki SM, Stabler SM, Monteiro MJ. Familial Alzheimer's disease presenilin-1 mutants potentiate cell cycle arrest. Neurobiol Aging. 2000 Nov-Dec;21(6):829-36. 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 P267S

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