Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PP2, PP3, BS1
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640406 G>T
dbSNP ID: rs201617677
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AGG to AGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5


This variant has been reported in several Chinese individuals with Alzheimer's disease with a relatively late onset. It was initially found using whole-exome sequencing to screen 15 patients from Chinese families with familial AD (Jiang et al., 2019). The proband was 60 years old at disease onset. His initial symptom was memory loss which progressed slowly, with irritability developing two years later. His mother died at approximately 90 years of age with cognitive impairment.

The variant was also found in a Chinese family in which the proband was diagnosed with AD and six family members, spanning three generations, were affected (Jia et al., 2020). The proband's age at onset was 72 years and the family's mean age at onset was 67.6 years. The variant was identified in four affected members, but its absence was not reported in an aged, unaffected member to demonstrate co-segregation. The proband's APOE genotype was E3/E3.

The variant was also reported in a Han Chinese man in Taiwan with depression and amnesic onset at age 51 (Lin et al., 2020). Family history for this individual was unavailable.

The variant was found in three population-based variant databases: the 1000 Genomes Project (0.0002), ExAC (0.0000659), and gnomAD (0.0000609), as well as in the East Asian subpopulation in ExAC (0.00009244) and Taiwan View (0.00033) (Jiang et al., 2019; Lin et al., 2020).

Neuropathological data are unavailable, but at age 59, the patient in Taiwan had posterior cortical atrophy and mild medial temporal atrophy, as assessed by MRI (Lin et al., 2020).

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) predicted this variant is damaging (Lin et al., 2020Xiao et al., 2021). Both Jiang et al. and Lin et al. classified this variant as of uncertain significance (Jiang et al., 2019; Lin et al., 2020).


Alzheimer's Disease : Uncertain Significance

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


Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.


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.


Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database. 

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 04 Oct 2023


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Paper Citations

  1. . Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing. Neurobiol Aging. 2019 Apr;76:215.e15-215.e21. Epub 2018 Dec 6 PubMed.
  2. . PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
  3. . Mutational analysis in familial Alzheimer's disease of Han Chinese in Taiwan with a predominant mutation PSEN1 p.Met146Ile. Sci Rep. 2020 Nov 13;10(1):19769. PubMed.
  4. . 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing. Neurobiol Aging. 2019 Apr;76:215.e15-215.e21. Epub 2018 Dec 6 PubMed.

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