Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73653581_73653583 TAT>---
dbSNP ID: rs63750879
Coding/Non-Coding: Coding
Mutation Type: 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).

In an in vitro assay with isolated proteins, a PSEN1 mutant protein missing an isoleucine at this position (I167del, nucleotide change unspecified) produced less Aβ42 than wild-type PSEN1, and Aβ40 production was undetectable (Sun et al., 2017). Several in silico algorithms  predicted this variant is damaging (Xiao et al., 2021). definitely pathogenic according to the algorithm proposed by Guerreiro et al., 2010.

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References

Paper Citations

1. 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.
2. 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.
3. 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.
4. 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.
5. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

External Citations

1. gnomAD v2.1.1

Further Reading

No Available Further Reading