Mutations

PSEN1 F386I

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73217152 T>A
Position: (GRCh37/hg19):Chr14:73683860 T>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTC to ATC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation was found in a Chinese family with a strong history of dementia (Shea et al., 2016). The family consisted of six siblings who were all affected, along with their father, who also had a clinical history consistent with AD. AD was diagnosed according to the NINCDS-ADRDA criteria for possible or probable disease. The three living siblings were all carriers of the L386I mutation. The average age of onset for the siblings was 49.8 years (range 45-60). Disease in this family presented as early memory problems, amnesia, and spatial disorientation. One of the siblings also developed epilepsy. 

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

Neuropathology

Neuropathology data are unavailable, but MRI imaging of two of the siblings demonstrated bilateral hippocampal atrophy, while a third sibling had severe medial temporal lobe atrophy (Shea et al., 2016).

Biological Effect

A study that examined a range of Aβ peptides produced by human embryonic kidney cells (HEK) expressing this mutant and lacking endogenous PSEN1 and PSEN2 revealed increased Aβ42/Aβ40 and decreased Aβ37/Aβ42, both indicators of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Of note, in this study, Aβ37/Aβ42 outperformed Aβ42/Aβ40 as a biomarker for distinguishing between control and AD samples. In addition, this variant increased levels of toxic Aβ43 approximately twofold compared with wildtype PSEN1.

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). 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.

PS3-S

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

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: 01 Dec 2022

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References

News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?

Paper Citations

  1. 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.
  2. Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
  3. 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.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. 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.

Other mutations at this position

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