Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3, BS2, BP2
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73685908 A>G
dbSNP ID: rs63750249
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATC to GTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was found in two sisters affected by early onset Alzheimer's disease (Rogaeva et al., 2001). They inherited the mutation from their mother, who was asymptomatic at age 55. Importantly, both sisters also carried, in trans, PSEN1 I143T, a variant which has been classified as pathogenic and which they inherited from their father. Information related to his clinical history was not reported. Both sisters developed symptoms before age 35.

I439V was also reported in an Italian individual with early onset AD who had a single first- or second-degree family member affected by late onset AD (Stella-Bartoletti et al., 2022). This carrier also had a mutation in the APP gene, A713T, which has been classified as a variant of uncertain significance or a risk factor for AD.

I439V is absent from the EVS and ExAC variant databases (Hsu et al., 2020).

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 a moderate increase in production of Aβ40 and Aβ42 compared with wildtype PSEN1, without altering the Aβ42/Aβ40 ratio (Sun et al., 2017). However, in mouse neuroblastoma cells lacking endogenous PSEN1 and PSEN2 and expressing APP695 (N2A695) and PSEN1 I439V, only Aβ42 secretion was increased and the Aβ42/Aβ40 ratio was moderately elevated (Hsu et al., 2020).

I439 is conserved between PSEN1 and PSEN2 and, although some silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Hsu et al., 2020, Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021). One group classified I439V as probably pathogenic (Hsu et al., 2020) and another as "diagnostic" (Stella-Bartoletti et al., 2022).

Pathogenicity

Alzheimer's Disease : Uncertain Significance*

*Note that affected carriers of this variant carried an additional, pathogenic mutation (PSEN1 I143T).

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. I439V: Functional observations are mixed, but together suggest modest damaging effect.

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.

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.

BS2-S

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.

BP2-P

Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Last Updated: 06 Jan 2023

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References

Mutations Citations

Paper Citations

Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
Bartoletti-Stella A, Tarozzi M, Mengozzi G, Asirelli F, Brancaleoni L, Mometto N, Stanzani-Maserati M, Baiardi S, Linarello S, Spallazzi M, Pantieri R, Ferriani E, Caffarra P, Liguori R, Parchi P, Capellari S. Dementia-related genetic variants in an Italian population of early-onset Alzheimer's disease. Front Aging Neurosci. 2022;14:969817. Epub 2022 Sep 5 PubMed.
Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 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 I439V

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