Overview

Pathogenicity: Alzheimer's Disease : Not Classified, Parkinsonism : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73186880 T>C
Position: (GRCh37/hg19):Chr14:73653588 T>C
dbSNP ID: rs63750577
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TCT to CCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was first reported in a patient who developed AD symptoms at age 27 and had a family history of AD (Irwin et al., 2013). Subsequently, the mutation was found in a man presenting with dystonia-parkinsonism at age 26, who later developed dementia and myoclonus (Carecchio et al., 2017). His IQ score (WAIS) was lower than normal (<45). Although levodopa initially improved his bradykinesia and rigidity, over subsequent years, his parkinsonism worsened, and he developed dementia, generalized myoclonic jerks, progressive aphasia, and dysphagia. The patient was bed-ridden with advanced dementia at age 31. In this case, the mutation, identified by whole exome sequencing, appeared to have arisen de novo—it was absent from the genomes of the parents and unaffected sister.

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

Neuropathology

Post-mortem brain tissue from the patient described in the first report displayed typical AD tau pathology, including widespread neuropil threads, neurofibrillary tangles, and neuritic plaques throughout cortical and, to a lesser degree, subcortical structures (Irwin et al., 2013). Although neuropathology data for the second patient is unavailable, a brain MRI scan at age 26, revealed bilateral hypointensity in the putamen and globus pallidus (Carecchio et al., 2017). A scan at age 31, showed signs of more extensive hypointensity, including the substantia nigra, and revealed frontotemporal cortical atrophy. In addition, SPECT imaging (with FP-CIT) showed a severe, bilateral deficit in nigrostriatal dopaminergic pathways, particularly in the putamen. Moreover, 18F-fuorodeoxyglucose PET imaging revealed hypometabolism in the striatum and posterior cingulate.

Biological Effect

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 (Carecchio et al., 2017; 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 only one affected carrier with AD has been reported—cosegregation data are lacking—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.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

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: 22 Feb 2022

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References

Paper Citations

Irwin DJ, Cohen TJ, Grossman M, Arnold SE, McCarty-Wood E, Van Deerlin VM, Lee VM, Trojanowski JQ. Acetylated tau neuropathology in sporadic and hereditary tauopathies. Am J Pathol. 2013 Aug;183(2):344-51. PubMed.
Carecchio M, Picillo M, Valletta L, Elia AE, Haack TB, Cozzolino A, Vitale A, Garavaglia B, Iuso A, Bagella CF, Pappatà S, Barone P, Prokisch H, Romito L, Tiranti V. Rare causes of early-onset dystonia-parkinsonism with cognitive impairment: a de novo PSEN-1 mutation. Neurogenetics. 2017 Jul;18(3):175-178. Epub 2017 Jun 29 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 S170P

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