Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73171022 T>G
Position: (GRCh37/hg19):Chr14:73637730 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTT to GTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was first reported in a Spanish patient who met clinical criteria for Alzheimer’s disease (Gómez-Tortosa et al., 2010). The patient began to experience memory problems at age 52. The patient did not have a known family history of dementia and segregation with disease could not be established because the patient’s only brother was cognitively healthy at age 55 and both parents had died at a young age. Her cognitive decline was described as fairly typical for AD, with no significant motor or atypical features.

The variant was subsequently reported in a 59-year-old Chinese man with familial AD (Gao et al., 2019). His symptoms began at age 52, and at age 59 included memory loss, executive dysfunction, disorientation, and impaired visuospatial skills. He also had motor dysfunction. His APOE genotype was APOE2/3. The proband's father and three of his four brothers were affected.

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

Neuropathology

Unknown.

Biological Effect

This mutant appears to reduce γ-processivity (Liu et al., 2021). Analysis of secreted Aβs in the conditioned media of human embryonic kidney cells lacking endogenous PSENs and expressing this mutant along with wildtype APP, revealed increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios. Interestingly, the authors also reported that Aβ42/40, Aβ38/42, and particularly Aβ37/42, ratios each correlated with reported ages of onset of clinical impairment across 16 PSEN1 mutations. This mutant also reduced total secreted Aβ levels.

Two studies predicted it to be probably damaging (PolyPhen), disease-causing (Mutation Taster), and to affect protein function (SIFT), with a CADD score of 24.9 (Gómez-Tortosa et al., 2010, G ao et al., 2019). However, Xiao and colleagues reported conflicting results using SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Pathogenic

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

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

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

Gómez-Tortosa E, Barquero S, Barón M, Gil-Neciga E, Castellanos F, Zurdo M, Manzano S, Muñoz DG, Jiménez-Huete A, Rábano A, Sainz MJ, Guerrero R, Gobernado I, Pérez-Pérez J, Jiménez-Escrig A. Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. PubMed.
Gao Y, Ren RJ, Zhong ZL, Dammer E, Zhao QH, Shan S, Zhou Z, Li X, Zhang YQ, Cui HL, Hu YB, Chen SD, Chen JJ, Guo QH, Wang G. Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease. Neurobiol Aging. 2019 May;77:154-157. Epub 2019 Jan 31 PubMed.
Liu L, Lauro BM, Wolfe MS, Selkoe DJ. Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 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 F105V

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