Overview

Pathogenicity: Alzheimer's Disease : Not Classified, Dementia with Lewy Bodies : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3, BP5
Clinical Phenotype: Alzheimer's Disease, Dementia with Lewy Bodies, Parkinsonism
Position: (GRCh38/hg38):Chr14:73217219 T>C
Position: (GRCh37/hg19):Chr14:73683927 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 11

Findings

This mutation was identified in two Italian sisters in a family with a history of late-onset Alzheimer's disease (Tedde et al., 2015). The proband met DSM-IV criteria for probable AD after experiencing symptom onset at the age of 73. Her younger sister, who also carried the mutation, was beginning to show signs of memory impairment at the age of 72. Segregation with disease could not be determined in this family, although there was a positive family history. The proband’s mother had died at age 72 following a stroke, and she reportedly suffered from mild cognitive impairment. Another sister had late-onset AD, starting at age 85, but refused genetic testing.

This variant was also reported in a Caucasian man who developed dementia with Lewy bodies with symptoms starting at age 60 (Tábuas-Pereira et al., 2022). His first symptoms were apathy and memory loss, particularly verbal memory, with emotional blunting and slowed processing of information. He had no known history of dementia or parkinsonism. Determining the contribution of I408T to disease in this case was complicated because the carrier was homozygous for a potentially pathogenic variant, R616W, in the ATP7B gene coding for copper-transporting ATPase 2. His APOE genotype was APOE3/E4.

PSEN1 I408T was found in the gnomAD variant database at a frequency of 0.000004 with an allele count of one (gnomAD v2.1.1, Sep 2021). It was also present in the gnomAD (non-neuro) dataset which excludes data from neurological studies, with a frequency of 0.000005 and an allele count of 1 (gnomAD v2.1.1 (non-neuro), Aug 2021).

Neuropathology

Neuropathological data are unavailable, but an MRI scan of the Italian proband showed marked enlargement of the lateral ventricles and hippocampal atrophy typical of AD (Tedde et al., 2015). In the case of the carrier with ATP7B R616W homozygosity, MRI showed bilateral temporal atrophy with mild leukoencephalopathy (Tábuas-Pereira et al., 2022). No MRI features of Wilson’s disease, a condition associated with ATP7B, were detected. Of note, this carrier’s levels of AD biomarkers in cerebrospinal fluid (Aβ42, tau, and phospho-tau) were consistent with AD. Additionally, a DaTSCAN revealed a deficit in dopamine uptake on the right side, consistent with the subject’s early onset parkinsonism.

Biological Effect

The biological effect of this variant is unknown, but 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 (Tedde et al., 2015, Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum because carriers had heterogenous phenotypes, including non-AD conditions, and the presence of a possibly pathogenic variant in another gene complicated the interpretation of results in one case.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PM1-P

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. I408T: Variant located at edge of mutational hot spot.

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.

BP5-P

Variant found in a case with an alternate molecular basis for disease.

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

Last Updated: 05 Jan 2023

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

Tedde A, Bartoli A, Piaceri I, Ferrara S, Bagnoli S, Serio A, Sorbi S, Nacmias B. Novel presenilin 1 mutation (Ile408Thr) in an Italian family with late-onset Alzheimer's disease. Neurosci Lett. 2016 Jan 1;610:150-3. Epub 2015 Nov 5 PubMed.
Tábuas-Pereira M, Guerreiro R, Kun-Rodrigues C, Almeida MR, Brás J, Santana I. Whole-exome sequencing reveals PSEN1 and ATP7B combined variants as a possible cause of early-onset Lewy body dementia: a case study of genotype-phenotype correlation. Neurogenetics. 2022 Oct;23(4):279-283. Epub 2022 Sep 17 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 I408T

Quick Links