Pathogenicity: Alzheimer's Disease : Uncertain Significance
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73673157 A>G
dbSNP ID: rs115865530
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: AAA to AGA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 9


This variant has been associated with late-onset Alzheimer's disease (LOAD) and mild cognitive impairment (MCI). It was first identified in two Chinese men with LOAD (Dong et al., 2017). Both men were in their 70s when they developed progressive memory decline, and both had a deceased parent who had suffered from similar cognitive impairment at a similar age. The mutation was absent from one cognitively normal family member (unspecified age) and from 100 normal individuals, and 100 unrelated patients with LOAD.

In a subsequent study, the variant was reported in four Chinese pedigrees, two whose affected members had either LOAD or MCI, and two who had only LOAD (Jia et al., 2020). Each family had between three and seven affected members, and between two and four affected mutation carriers, but only one also had an unaffected, non-carrier who was older than the age of onset of the carriers. This non-carrier remained cognitively healthy at age 73, past the ages of AD onset, 65 and 69, of the two known mutation carriers. Across all families, most individuals had an APOE3/E3 genotype, except for three individuals with an APOE3/E2 genotype, and two with an APOE3/E4 genotype.

The variant was also found in a Vietnamese woman who began experiencing AD symptoms at age 59 (Tong et al., 2021). She was  homozygous for the APOE4 allele. Of 10 family members, only she and her mother, who developed dementia at age 70, were affected.

The variant was present at a frequency of 0.0001344 with an allele count of 38 in the gnomAD variant database (gnomAD v2.1.1, July 2021) and at a frequency of 0.0001439 with an allele count of 33 in the subdivision of the database that excludes data from neurological studies (gnomAD v2.1.1 (non-neuro), July 2021).


Biological Effect
Increased Aβ42 and reduced Aβ40 levels, resulting in an increased Aβ42/Aβ40 ratio, were detected in the conditioned media of cultured cells transfected with plasmids carrying the K311R mutation (Dong et al., 2017). Phosphorylated tau levels were also increased in cell lysates.

However, in silico algorithms (LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, PANTHER, Mutpred2 and Reve) yielded conflicting results (Jia et al., 2020Xiao et al., 2021). Jia and colleagues reported that only two of the five algorithms they applied predicted a damaging effect, and the PHREDD CADD score was 14.34.

Last Updated: 21 Sep 2021


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Paper Citations

  1. . A Novel PSEN1 K311R Mutation Discovered in Chinese Families with Late-Onset Alzheimer's Disease Affects Amyloid-β Production and Tau Phosphorylation. J Alzheimers Dis. 2017;57(2):613-623. 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. . Genetic analysis of Vietnamese patients with early-onset Alzheimer's disease. Int J Neurosci. 2021 Feb 21;:1-8. 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.

External Citations

  1. gnomAD v2.1.1
  2. gnomAD v2.1.1 (non-neuro)

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A Novel PSEN1 K311R Mutation Discovered in Chinese Families with Late-Onset Alzheimer's Disease Affects Amyloid-β Production and Tau Phosphorylation. J Alzheimers Dis. 2017;57(2):613-623. PubMed.

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