Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73170974 G>T
Position: (GRCh37/hg19):Chr14:73637682 G>T
dbSNP ID: rs63750815
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to TTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This is a rare mutation identified in a family from Barcelona, Spain. The reported pedigree included three affected family members over two generations who developed early onset Alzheimer’s disease. The clinical presentation in this family was notable for early and severe personality changes (e.g., apathy, irritability, paranoia) and early behavioral disturbances prior to cognitive impairment. Age of onset in this family ranged from 46 to 51 years. V89L is considered likely pathogenic due to the presence of the mutation in the proband and an affected sibling and its absence in a healthy sibling. Genetic analysis was not possible in the proband’s affected father as he had already died (Queralt et al., 2002; Lleó et al., 2002). The variant was absent from the gnomAD variant database (May 2021).

Neuropathology

Postmortem analysis of the proband’s brain confirmed the AD diagnosis. Neurofibrillary tangles and neuritic plaques with dystrophic neurites corresponding to stage VI of Braak and Braak were observed. Plaques were common in the hippocampus, amygdala, and neocortex. Tangles were most abundant in the neocortex and hippocampus, but were also found in the striatum, thalamus, and midbrain. Blood vessels in the cortex showed signs of amyloid angiopathy. Overall, the brain showed moderate cortical atrophy and enlarged ventricles (Queralt et al., 2002).

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant (nucleotide change unspecified) to cleave the APP-C99 substrate revealed it produces less Aβ42, and even less Aβ40, than wild-type PSEN1, resulting in an elevated Aβ42/Aβ40 ratio (Sun et al., 2017).

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 : Pathogenic

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-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. V89L (G>T): Aβ42/Aβ40 ratio increased, but production of both peptides decreased.

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.

PP1-M

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. V89L (G>T): At least one family with 2 affected carriers and >=1 unaffected noncarriers.

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: 27 Jun 2022

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References

Paper Citations

Queralt R, Ezquerra M, Lleó A, Castellví M, Gelpí J, Ferrer I, Acarín N, Pasarín L, Blesa R, Oliva R. A novel mutation (V89L) in the presenilin 1 gene in a family with early onset Alzheimer's disease and marked behavioural disturbances. J Neurol Neurosurg Psychiatry. 2002 Feb;72(2):266-9. PubMed.
Lleó A, Blesa R, Queralt R, Ezquerra M, Molinuevo JL, Peña-Casanova J, Rojo A, Oliva R. Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain. Arch Neurol. 2002 Nov;59(11):1759-63. 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.
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 V89L (G>T)

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