Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3, BS3, BP5
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73186875 T>C
Position: (GRCh37/hg19):Chr14:73653583 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATA to ACA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This variant was found in an exome sequencing study of 141 individuals with late-onset Alzheimer’s disease and 179 elderly controls who did not have evidence of neuropathology at the time of their deaths. The mutation carrier was a Caucasian man who was diagnosed with AD at the age of 86. His APOE genotype was ε2/ε4. He died at age 94 with extensive neuropathology (Braak stage V). He had no known family history of dementia (Sassi et al., 2014).

The variant was absent from the gnomAD variant database (gnomAD v2.1.1, June 2021).

Neuropathology

The individual carrying this variant was found to have severe neuropathology consistent with AD (Braak V) (Sassi et al., 2014).

Biological Effect

The biological effect of this variant, if any, is uncertain. Mouse neuroblastoma cells expressing this variant secreted similar amounts of Aβ42 and Aβ40 compared with cells expressing wild-type PSEN1, and had a similar Aβ42/Aβ40 ratio (Hsu et al., 2020). However, in an in vitro assay with isolated proteins, this mutant produced less Aβ42 than the wild-type protein, and Aβ40 production was undetectable (Sun et al., 2017). Several in silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Sassi et al., 2014, Hsu et al., 2020, Xiao et al., 2021), however, the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021). Sassi and colleagues classified the variant as probably pathogenic (Sassi et al., 2014), while Hsu and co-workers classified it as not pathogenic (Hsu et al., 2020).

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.

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.

BS3-P

Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing. I168T: Findings were mixed, but suggest Aβ40 and Aβ42 production are unchanged or reduced.

BP5-P

Variant found in a case with an alternate molecular basis for disease. I168T: Carrier had LOAD and an APOE4 allele.

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

Last Updated: 18 Mar 2022

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References

Paper Citations

Sassi C, Guerreiro R, Gibbs R, Ding J, Lupton MK, Troakes C, Al-Sarraj S, Niblock M, Gallo JM, Adnan J, Killick R, Brown KS, Medway C, Lord J, Turton J, Bras J, Alzheimer's Research UK Consortium, Morgan K, Powell JF, Singleton A, Hardy J. Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease. Neurobiol Aging. 2014 Dec;35(12):2881.e1-2881.e6. Epub 2014 Jun 16 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 I168T

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