Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM4, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73186868_73186870 CTT>---
Position: (GRCh37/hg19):Chr14:73653576_73653578 CTT>---
dbSNP ID: rs63751458
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: Deletion
Codon Change: CTT to ---
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This deletion of three nucleotides (one amino acid) was detected in a woman who developed insidious onset of memory impairment at age 38 (Knight et al., 2007). Her general short-term memory was affected and the report noted particular difficulties with topographical memory (the ability to navigate around a familiar environment) as well as in the ability to comprehend numbers and arithmetic. She did not have myoclonus or extrapyramidal signs. Her mother had died at the age of 46 with dementia, after suffering from progressive memory impairment from an unknown age. The patient's father had a diagnosis of vascular dementia at age 83 years. Segregation with disease could not be assessed as DNA was available only from the patient; however, it was noted that the deletion was absent in 100 normal controls. It was also absent from the gnomAD variant database (gnomAD v2.1.1, June 2021).

Neuropathology

Unknown. MRI showed generalized, symmetrical cerebral atrophy, which was most prominent in the medial temporal lobes (Knight et al., 2007).

Biological Effect

In an in vitro assay with isolated proteins, this mutant produced less Aβ42 than wild-type PSEN1, and Aβ40 production was undetectable (Sun et al., 2017). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news). Moreover, 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).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, 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.

PS3-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. L166del: Aβ42/Aβ40 ratio increased, but production of both peptides decreased.

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. L166del: 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.

PM4-P

Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. L166del: 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: 22 Feb 2022

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References

News Citations

Paper Citations

Knight WD, Kennedy J, Mead S, Rossor MN, Beck J, Collinge J, Mummery C. A novel presenilin 1 deletion (p.L166del) associated with early onset familial Alzheimer's disease. Eur J Neurol. 2007 Jul;14(7):829-31. 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.
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 L166del

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