Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73683860 T>A
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, 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

Unknown. MRI imaging of two of the siblings demonstrated bilateral hippocampal atrophy, while a third sibling had severe medial temporal lobe atrophy.

Biological Effect

The biological effect of this variant is 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 (Xiao et al., 2021). The site of the F386I mutation is adjacent to D385, a critical aspartate in the active site (Shea et al., 2016).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum because data for either a pathogenic or benign classification are lacking: it was found in a single affected family without clear evidence of cosegregation or a functional effect, and it 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.

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

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.
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 F386I

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