Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198082 C>A
Position: (GRCh37/hg19):Chr14:73664790 C>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACA to AAA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in a Turkish man diagnosed with early onset Alzheimer’s disease (Eryilmaz et al., 2021). He had no known family history of the disease. His age of onset was 29 and he was described as having mild to moderate cognitive impairment. The mutation was found by heteroduplex analysis using DNA from 20 healthy controls, followed by sequence analysis of four AD-relevant genes, including PSEN1. It was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology
Neuropathology data are unavailable, but an MRI scan was reported as showing alterations consistent with AD.

Biological effect
The biological effect of this variant is unknown. In silico algorithms predicted structural and functional alterations. As reported by the authors, Mutation Taster classified it as disease-causing and predicted impaired cleavage specificity and increased production of Aβ42 (Eryilmaz et al., 2021). The UMD-Predictor gave it a 93 percent pathogenicity score. Moreover, SWISS-MODEL predicted structural disruption and I-Mutant suggested a large decrease in the protein’s stability. T274 is within a region that appears to undergo a dramatic conformational change as a result of APP binding (Zhou et al., 2019; Jan 2019 news). The region moves towards the APP β-strand, forming a new α-helix (TM6a) that interacts with residues in PSEN1's second transmembrane domain.

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-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. T274K: 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.

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: 28 Feb 2022

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References

News Citations

Paper Citations

Eryilmaz IE, Bakar M, Egeli U, Cecener G, Yurdacan B, Colak DK, Tunca B. Evaluation of the Clinical Features Accompanied by the Gene Mutations: The 2 Novel PSEN1 Variants in a Turkish Early-onset Alzheimer Disease Cohort. Alzheimer Dis Assoc Disord. 2021 Jul-Sep 01;35(3):214-222. 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.

Mutations

PSEN1 T274K

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