Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173667 C>T
Position: (GRCh37/hg19):Chr14:73640375 C>T
dbSNP ID: rs63750907
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACT to ATT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was detected in a French kindred (Alz 047), reported to have four affected individuals over three generations. The symptoms were described as being fairly typical of Alzheimer's disease, with onset ranging from age 37 to 46. Segregation with disease was confirmed (Campion et al., 1999).

This mutation was later found in four members of a large American kindred affected by very early onset dementia (Denvir et al., 2015). The reported pedigree shows 19 affected members over five generations in a pattern indicative of autosomal-dominant inheritance. All affected members developed cognitive decline in their mid- to late 20s. In addition to cognitive impairment, the four known mutation carriers, a mother-daughter dyad and two cousins of the daughter, exhibited features atypical of AD, including limb spasticity and early loss of expressive speech. In brief, the daughter first experienced cognitive decline at age 27. She developed expressive aphasia, dysphagia, and motor impairment due to prominent myoclonic jerks and increased muscle tone. At the time of the report, her mother was 57 years old and had advanced dementia. She had been admitted to a nursing home at age 38. Little is known about her clinical history other than that she had seizures by age 35 and evidence of cognitive impairment prior to that. Both the mother and daughter had APOE genotypes of ε3/ε4. Not much is known about the two affected cousins: One died at age 36 and the other was alive at age 37.

The mutation was also found in a screen involving whole-exome sequencing of 15 unrelated Chinese patients with familial AD (Jiang et al., 2019). The proband presented with amnestic symptoms typical of AD.

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

Neuropathology

Unknown.

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it produces less Aβ40 and more Aβ42 than wild-type PSEN1, resulting in a greater than twofold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). Interestingly, T147 closely contacts APP as revealed by a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment (Zhou et al., 2019; Jan 2019 news). The residue contributes to APP but not Notch binding (Yang et al., 2019).

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 (Denvir et al., 2015; Xiao et al., 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.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. T147I: 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. T147I: 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.

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: 22 Feb 2022

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References

News Citations

Paper Citations

Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
Denvir J, Neitch S, Fan J, Niles RM, Boskovic G, Schreurs BG, Primerano DA, Alkon DL. Identification of the PS1 Thr147Ile Variant in a Family with Very Early Onset Dementia and Expressive Aphasia. J Alzheimers Dis. 2015 May 30;46(2):483-90. PubMed.
Jiang B, Zhou J, Li HL, Chen YG, Cheng HR, Ye LQ, Liu DS, Chen DF, Tao QQ, Wu ZY. Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing. Neurobiol Aging. 2019 Apr;76:215.e15-215.e21. Epub 2018 Dec 6 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.
Yang G, Zhou R, Zhou Q, Guo X, Yan C, Ke M, Lei J, Shi Y. Structural basis of Notch recognition by human γ-secretase. Nature. 2019 Jan;565(7738):192-197. Epub 2018 Dec 31 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 T147I

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