Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73217160 C>G
Position: (GRCh37/hg19):Chr14:73683868 C>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTC to TTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

The F388L mutation was found in a Chinese family with a strong history of dementia (Zhan et al., 2016). The family consisted of five siblings, three of whom had a history of cognitive impairments, as did the father. The proband was diagnosed with AD according to the NINCDS-ADRDA criteria for possible or probable AD. The proband’s symptoms began with progressive memory impairment. Subsequently she developed psychosis, paranoid delusions, and impairments in verbal expression and visuospatial tasks. The average age of onset in the family was 43 years (range 42-45). The father and one sibling both died three years after onset (at ages 45 and 48, respectively).

The two surviving affected siblings were carriers of the F388L mutation while the unaffected siblings were not carriers, indicating segregation with disease. Other mutations in APP, PSEN1, and PSEN2 known to be associated with familial AD were not found in this family. Additionally, the proband was homozygous for APOE3 and did not have any TREM2 mutations associated with AD risk. The F388L mutation was absent from 360 healthy Chinese control subjects and from the gnomAD variant database (gnomAD v2.1.1, August 2021).

Neuropathology

Unknown.

Biological Effect

In a cell line stably expressing the APP₇₅₁ isoform, expression of presenilin-1 with the F388L mutation increased the amount of Aβ42 and the Aβ42/Aβ40 ratio relative to cells expressing wildtype presenilin-1 (Zhan et al., 2016).

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that F388 helps form a shallow hydrophobic pocket for part of the C-terminal portion of the APP transmembrane helix (Zhou et al., 2019; Jan 2019 news). Moreover, 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 (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.

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. F388L: 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.

PP1-M

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. F388L: At least one family with 2 affected carriers and >=1 unaffected noncarriers.

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

News Citations

Paper Citations

Zhan Y, Zheng H, Wang C, Rong Z, Xiao N, Ma Q, Zhang YW. A novel presenilin 1 mutation (F388L) identified in a Chinese family with early-onset Alzheimer's disease. Neurobiol Aging. 2017 Feb;50:168.e1-168.e4. Epub 2016 Oct 15 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.
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 F388L

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