Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73678582 C>T
dbSNP ID: rs63751164
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ACA to ATA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 10

Findings

This variant was first reported in one person with Alzheimer’s disease in a large genetic screen. Clinical details and family history information were not reported (Rogaeva et al., 2001).

The variant was subsequently identified in a 46-year-old man with a five-year history of cognitive decline (Lee et al., 2006). He had a family history consistent with AD: Two of his father’s siblings developed memory impairment in their early 40s, and both had died approximately five years later. His father had died of an accident at age 32, so whether he would have developed dementia is unknown.

This case is unusual because in addition to carrying the T354I variant, the proband carried a second presenilin-1 variant, the A431E (Jalisco) mutation. His father’s family had ancestral ties to the Mexican state of Jalisco. The Jalisco mutation is pathogenic and alone could account for the patient’s early onset AD. The proband’s 81-year-old grandmother carried the T354I variant, but not the Jalisco mutation. She had cognitive symptoms, including deficits in recent memory and orientation, and was considered to have moderate dementia. Her APOE genotype was 3/4.

The variant was also found in a woman from Uruguay who developed dementia at 58 years of age (Marini et al., 2013). Her decline was very rapid, with psychiatric symptoms, including anxiety and agitation, characterizing the early stages of disease. No medical information on her biological family was available, so the authors were unable to assess whether the variant segregated with disease.

This variant was found in the gnomAD variant database with an allele count of two and frequency of 0.000007953 (gnomAD v2.1.1, Sep 2021).

Neuropathology

Neuropathological data are unavailable. However, brain imaging showed severe generalized atrophy in one case (Lee et al., 2006), and hypometabolism in the parietotemporal cortex typical of AD in another (Marini et al., 2013). CSF levels of Aβ42, total-tau, and phospho-tau were consistent with AD in the latter case.

Biological Effect

An in vitro assay using purified proteins to test the ability of the variant to cleave the APP-C99 substrate revealed decreased Aβ42 and Aβ40 production, with a more robust drop in Aβ42 levels, and a resulting decrease in the Aβ42/Aβ40 ratio (Sun et al. 2017). In silico algorithms to predict the effects of this variant on protein function (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) yielded conflicting results (Xiao et al., 2021), but the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).

Lee and colleagues noted this variant may be a rare benign polymorphism (Lee et al., 2006). Moreover, Koriath and colleagues described it as most likely having reduced penetrance (calculated at 5.2%; 0.4%, 64.4% CI; Koriath et al., 2018).

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References

Paper Citations

1. 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.
2. Lee P, Medina L, Ringman JM. The Thr354Ile substitution in PSEN1:: disease-causing mutation or polymorphism?. Neurology. 2006 Jun 27;66(12):1955-6. PubMed.
3. Marini S, Lucidi G, Tedde A, Bessi V, Nacmias B. A case of atypical early-onset Alzheimer's disease carrying the missense mutation Thr354Ile in exon 10 of the PSEN1 gene. Neurol Sci. 2012 Dec 2; PubMed.
4. 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.
5. 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.
6. Koriath C, Kenny J, Adamson G, Druyeh R, Taylor W, Beck J, Quinn L, Mok TH, Dimitriadis A, Norsworthy P, Bass N, Carter J, Walker Z, Kipps C, Coulthard E, Polke JM, Bernal-Quiros M, Denning N, Thomas R, Raybould R, Williams J, Mummery CJ, Wild EJ, Houlden H, Tabrizi SJ, Rossor MN, Hummerich H, Warren JD, Rowe JB, Rohrer JD, Schott JM, Fox NC, Collinge J, Mead S. Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.

Other Citations

1. A431E (Jalisco)

External Citations

1. gnomAD v2.1.1
2. CADD v.1.6

Further Reading

No Available Further Reading