Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227076603 G>T
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTG to TTG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 8


This mutation has been reported in multiple East Asian individuals and families affected by Alzheimer's disease. In one family, the mutation was found to segregate with disease. However, the mutation has also been identified in one healthy, aged family member, and in the gnomAD variant database at a moderately high level in the East Asian population.

This mutation was first reported in a Korean individual with symptoms consistent with Alzheimer’s disease. She developed progressive memory impairment at age 69 followed by visuospatial dysfunction and difficulties with calculation and executive functioning. She had a 20-year history of a mild tremor in her right hand, which was not progressive. Family history was not available. The mutation was absent in 614 control chromosomes and in the other 89 AD patients screened in the study (Youn et al., 2014). Two years later, another Korean carrier was reported who suffered from memory loss and anomia, with age at onset of 54 and no first-degree family history of dementia (An et al., 2016).

This mutation was also detected in two unrelated Chinese individuals with Alzheimer’s disease (Shi et al., 2015). One of the mutation carriers, a woman who developed memory loss at age 64, had a family history of dementia. Her father was diagnosed with dementia at age 70, and he died at 80. Segregation with disease could not be assessed. The second mutation carrier, a man who developed memory loss at age 63, had apparently sporadic early onset AD. His APOE genotype was E3/E3.

Two additional Chinese mutation carriers were reported in a subsequent study (Xu et al., 2018). One was diagnosed with AD and began suffering from memory loss and apathy at age 52. The other was diagnosed with AD/FTD. Symptoms included forgetfulness, apathy, and irritability, with age at onset of 54 years. Of note, this patient's father carried the mutation and had an APOE3/4 genotype, but was unaffected.

Of note, two families of the Chinese Familial Alzheimer’s Disease Network were subsequently identified as carrying the mutation and, in one of them, the variant cosegregated with disease (Jia et al., 2020). In this family, one affected carrier was diagnosed with AD and another with mild cognitive impairment. Ages at onset were 53 and 42, respectively. The healthy non-carriers were siblings of the carriers, aged 63 and 65. All individuals were APOE3 homozygotes. The second family included three affected carriers whose AD ages at onset ranged from 58 to 61 years. Two of these individuals carried an APOE4 allele.

This variant is found in the gnomAD variant database at a global frequency of 0.0002581 and a frequency of 0.003559 in the East Asian population, with 71 of 73 reported heterozygotes being of East Asian ancestry (gnomAD v2.1.1, Nov 2021).


MRI scans of both Korean women showed cortical atrophy, in one case it was described as diffuse and in the other as centered around the parietal and temporal lobes (Youn et al., 2014, An et al., 2016). In one case, mild white-matter hyperintensities were noted (Youn et al., 2014). FDG-PET imaging in both cases showed hypometabolism in the bilateral temporoparietal lobes and, in one case, the precuneus was also affected (Youn et al., 2014).  Neuroimaging of one of the Chinese mutation carriers at age 65 showed diffuse cortical atrophy and widespread hypometabolism. PIB-PET showed amyloid deposits in the frontal, temporal, and parietal lobes, as well as in the cingulate, precuneus and striatum (Shi et al., 2015).

Biological Effect

The biological effect of this variant is unknown. Structural changes were predicted in silico, especially at amino acids 214, 219, and 220 (Youn et al., 2014). Consistently, the variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 2021). However, not all in silico algorithms predicted damaging effects (Xu et al., 2018, Jia et al., 2020). 

One group described the variant  as "most likely benign" or causing an "only small increase in risk" based on its allele count and frequency in the gnomAD variant database (Koriath et al., 2018). The penetrance was calculated to be two percent or less. Hsu and colleageus classified it as "Not Pathogenic; Risk Factor" (Hsu et al., 2020).

Last Updated: 01 Dec 2021


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Paper Citations

  1. . Probable novel PSEN2 Val214Leu mutation in Alzheimer's disease supported by structural prediction. BMC Neurol. 2014 May 15;14:105. PubMed.
  2. . A genetic screen of the mutations in the Korean patients with early-onset Alzheimer's disease. Clin Interv Aging. 2016;11:1817-1822. Epub 2016 Dec 15 PubMed.
  3. . Clinical and neuroimaging characterization of Chinese dementia patients with PSEN1 and PSEN2 mutations. Dement Geriatr Cogn Disord. 2015;39(1-2):32-40. Epub 2014 Oct 15 PubMed.
  4. . The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia. Aging Dis. 2018 Aug;9(4):696-705. PubMed.
  5. . PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
  6. . Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
  7. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Probable novel PSEN2 Val214Leu mutation in Alzheimer's disease supported by structural prediction. BMC Neurol. 2014 May 15;14:105. PubMed.


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