Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PM4, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73186873_73186875 TAT>---
Position: (GRCh37/hg19):Chr14:73653581_73653583 TAT>---
dbSNP ID: rs63750879
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: Deletion
Codon Change: ATT.ATA to ATA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

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 45 years. Five members of the individual’s family, spanning two generations, were diagnosed with AD, with a mean age of onset of 52 years. DNA was unavailable from these relatives, however, so co-segregation of the mutation and disease could not be demonstrated. The mutation was absent from the gnomAD variant database (gnomAD v2.1.1, June 2021).

A subsequent study, also examining British AD patients, reported the protein mutation (nucleotide change unspecified) in a family with five affected members and a mean age at onset of 54 years (Ryan et al., 2016). Extrapyramidal signs were identified in one of two members. It is uncertain if the same family was studied in the two reports.

Neuropathology
Unknown.

Biological Effect
This mutation is a deletion of three nucleotides: the third base pair of codon I167 and the first and second base pairs of codon I168, resulting in the in-frame deletion of an isoleucine. In several reports, this mutation is referred to as I167del, but following the HGVS nomenclature guidelines (v. 20.05), we refer to it as I168del, assigning the deletion to the most C-terminal position (3’ rule).

A study that examined the full set of Aβ peptides generated by a PSEN1 mutant protein missing an isoleucine at this position (I167del, nucleotide change unspecified) in transfected cells revealed an increase in toxic Aβ43 and a decrease in Aβ37, an indicator of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Importantly, like known pathogenic mutations, this variant decreased the Aβ37/Aβ42 ratio, a measurement that outperformed the Aβ42/Aβ40 ratio as a biomarker for distinguishing between control and AD samples. In an in vitro assay with isolated proteins, this mutant protein (nucleotide change unspecified) produced less Aβ42 than wild-type PSEN1, and Aβ40 production was undetectable (Sun et al., 2017). However, the latter assay appears to be limited in its cleavage efficiency given that 68 of 138 mutant recombinant PSEN1 enzymes 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).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because it is unclear if more than one affected carrier has been reported—cosegregation data are lacking—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.

PS1-S

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

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.

PM4-P

Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. I168del (TATdel): Single amino acid deletion.

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: 08 Nov 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.
Ryan NS, Nicholas JM, Weston PS, Liang Y, Lashley T, Guerreiro R, Adamson G, Kenny J, Beck J, Chavez-Gutierrez L, de Strooper B, Revesz T, Holton J, Mead S, Rossor MN, Fox NC. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. Epub 2016 Oct 21 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.
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 I168del (TATdel)

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