Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73217154 C>A
dbSNP ID: rs1555358095
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTC to TTA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation was originally found to segregate with dementia in a Japanese family (Yagi et al., 2014). The proband, who was diagnosed with probable AD, and her affected brother were identified as mutation carriers. The father and another brother were also affected, but their genotypes are unknown. The mother was unaffected at age 80 and did not carry the mutation. Ages at onset for the proband and her brother were 40 and 52 years, respectively. The mutation was absent from 112 Japanese control subjects and 147 patients with diseases other than AD. It was also absent from the variant databases dbSNP137, gnomAD, and 1000 genomes.

A subsequent study identified the variant in a large South Asian family with early onset AD (Eger et al., 2022). The proband was a woman who began experiencing memory loss at age 44 and was diagnosed with AD at age 45. The range of disease onset in this family was from 38 to 57 years of age. Segregation with disease was clearly established: three affected members carried the mutation, while two non-carriers, well past the range of disease onset at 66 and 76 years old, remained cognitively healthy.

Neuropathology
Four carriers from the South Asian family had brain imaging and CSF biomarker profiles consistent with AD (Eger et al., 2022). Of note, one of these carriers was cognitively healthy at age 36, but his florbetaben PET scan, like that of the proband, was amyloid positive with high uptake in the striatum.

Biological Effect
The biological effects of the mutation are 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 (Yagi et al., 2014, Xiao et al., 2021). Of note, F386 is adjacent to D385, an aspartate thought to be critical for PSEN1's enzymatic active site (Shea et al., 2016).

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.

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.

PP1-S

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. F386L: Cosegregation demonstrated in >1 family.

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)

Research Models

A neuronal cell model has been generated directly from adult fibroblasts isolated from a 47-year-old female carrier (Chou et al., 2023, Jun 2023 news). Unlike neurons differentiatd from induced pluripotent stem cells, these transdifferentiated neurons, called tNeurons, retain epigenetic marks of aging.

Last Updated: 26 Jun 2023

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References

News Citations

Paper Citations

Chou C-C, Vest R, Prado MA, Wilson-Grady J, Paulo JA, Shibuya Y, Moran-Losada P, Lee T-T, Luo J, Gygi SP, Kelly JW, Finley D, Wernig M, Wyss-Coray T, Frydman J. Proteostasis and lysosomal quality control deficits in Alzheimer's disease neurons. 2023 Mar 27 10.1101/2023.03.27.534444 (version 1) bioRxiv.
Yagi R, Miyamoto R, Morino H, Izumi Y, Kuramochi M, Kurashige T, Maruyama H, Mizuno N, Kurihara H, Kawakami H. Detecting gene mutations in Japanese Alzheimer's patients by semiconductor sequencing. Neurobiol Aging. 2014 Jul;35(7):1780.e1-5. Epub 2014 Jan 25 PubMed.
Eger SJ, Le Guen Y, Khan RR, Hall JN, Kennedy G, Zaharchuk G, Couthouis J, Brooks WS, Velakoulis D, Napolioni V, Belloy ME, Dalgard CL, Mormino EC, Gitler AD, Greicius MD. Confirming Pathogenicity of the F386L PSEN1 Variant in a South Asian Family With Early-Onset Alzheimer Disease. Neurol Genet. 2022 Feb;8(1):e647. Epub 2021 Dec 7 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.
Shea YF, Chan AO, Chu LW, Lee SC, Law CY, See CH, Yiu KL, Chiu PK. Novel presenilin 1 mutation (p.F386I) in a Chinese family with early-onset Alzheimer's disease. Neurobiol Aging. 2017 Feb;50:168.e9-168.e11. Epub 2016 Oct 15 PubMed.

Mutations

PSEN1 F386L

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