Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659570 A>C
dbSNP ID: rs63751320
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TAT to TCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7


This mutation was found in a young man with rapid-progressing dementia emerging at 25 years of age, (Miklossy et al., 2003). His initial symptoms included delusional thinking, obsessive-compulsiveness, and aggressiveness. Memory loss with changes in judgement capacity, dysarthria, apathy, agraphia, and acalculia developed rapidly in the subsequent year. He also presented with corticospinal signs (tetraspasticity, bilateral Babinski), athetosis, myoclonus, static and kinetic cerebellar ataxia astereognosia, and deficits in proprioception and graphesthesia. The man died three years after disease onset. The proband’s mother also died at an early age, 32, after disease onset at age 30. She suffered from disorientation, verbal perseverations, laconic speech, stereotypic behavior, apraxia, catatonic postures, dysarthria, visual field deficits, static and kinetic cerebellar ataxia, and corticospinal and mild extrapyramidal signs. The mutation was absent from 100 unrelated individuals and from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology was consistent with AD, but particularly widespread and severe (Suvà et al., 1999; Miklossy et al., 2003). In the proband, diffuse, predominantly cortical atrophy was observed (Braak grade VI). Abundant plaque and tangle formation was found in the entorhinal cortex, hippocampus, as well as in the frontal and parietal associative cortices. Pathology in the primary motor cortex correlated well with the pyramidal changes, including tetraspasticity. Numerous plaques and tangles were also found in the basal ganglia, thalamus, and the substantia nigra. Moreover, neurofibrillary tangles were reported in the locus coeruleus, raphe nuclei, and the pontine reticular formation, and plaques were found in the mesencephalon, pons, medulla oblongata, cervical level of the spinal cord, and cerebellum. Plaque types included cotton-wool, amorphous, and mature. Clinical reports from the proband’s mother indicate she also had neuropathology consistent with AD.

Biological Effect

Elevated levels of both Aβ40 and Aβ42 were detected in frontal cortex by immunoblot and ELISA (Miklossy et al., 2003). In HEK293 cells stably overexpressing Swedish (sw) mutant APP in combination with the mutant protein, very high levels of Aβ42 were observed, as well as production of Aβ43 (Tambauer et al., 2020). Presenilin endoproteolysis, however, was normal. In an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate, an approximately 8-fold increase in the Aβ42/Aβ40 ratio was reported, although production of both peptides was reduced compared with wild-type PSEN1 (Sun et al., 2017). Cross-linking experiments revealed disrupted interactions between the mutant and the Aβ peptide precursor C99 (Trambauer et al., 2020). Y256 is proximal to the PSEN1 active site and the authors suggest this altered positioning likely affects the strength of C99–γ‐secretase interactions which plays a key role in the carboxy‐terminal trimming pathway and the generation of pathogenic longer Aβ species.

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) consistently predicted this variant is damaging (Xiao et al., 2021). These authors classified the variant as pathogenic using the ACMG-AMP guidelines (Richards et al., 2015).

Last Updated: 10 Sep 2021


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Paper Citations

  1. . Two novel presenilin-1 mutations (Y256S and Q222H) are associated with early-onset Alzheimer's disease. Neurobiol Aging. 2003 Sep;24(5):655-62. PubMed.
  2. . Primary motor cortex involvement in Alzheimer disease. J Neuropathol Exp Neurol. 1999 Nov;58(11):1125-34. PubMed.
  3. . Aβ43-producing PS1 FAD mutants cause altered substrate interactions and respond to γ-secretase modulation. EMBO Rep. 2020 Jan 7;21(1):e47996. Epub 2019 Nov 25 PubMed.
  4. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
  5. . 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.
  6. . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Two novel presenilin-1 mutations (Y256S and Q222H) are associated with early-onset Alzheimer's disease. Neurobiol Aging. 2003 Sep;24(5):655-62. PubMed.

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