Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease, Ataxia
Reference Assembly: GRCh37/hg19
Position: Chr14:73640374 A>C
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ACT to CCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5


This mutation was detected in an Italian individual with early onset cognitive impairment associated with prominent cerebellar ataxia. The patient was 32 years old when she began to experience mild forgetfulness and compulsive behavior. Within months, significant motor problems developed involving both fine motor skills and gait. She developed myoclonic jerks and fell frequently. As cognitive impairment progressed, speech became progressively slower and slurred. By age 37 she was bedridden due to orthostatic hypotension. She developed generalized tonic-clonic seizures and bulbar symptoms. She died at age 40.

The patient did not have a family history of dementia or ataxia. Segregation of the T147P mutation with disease could not be assessed, but it was shown to be absent in 600 unrelated controls. Other genes known to cause cognitive impairment and/or ataxia were screened—APP, PSEN2, MAPT, PGRN, C9ORF72, PRNP, FRDA, SCA1, SCA2, SCA3, SCA17—no additional mutations were found (Testi et al., 2014).

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).


Although neuropathology data are unavailable, neuroimaging showed widespread cortical atrophy, as well as atrophy in the medial temporal lobes, with less severe cerebellar atrophy (Testi et al., 2014).

Biological Effect

Although the biological effects of this mutant are unknown, it was predicted to be probably damaging by in silico analysis with SIFT and PolyPhen-2 programs (Testi et al., 2014). Moreover, T147 closely contacts APP as revealed by a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment (Zhou et al., 2019; Jan 2019 news). Interestingly, the residue contributes to APP but not Notch binding (Yang et al., 2019).

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).

Last Updated: 09 Sep 2021


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News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . A novel PSEN1 mutation in a patient with sporadic early-onset Alzheimer's disease and prominent cerebellar ataxia. J Alzheimers Dis. 2014;41(3):709-14. PubMed.
  2. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  3. . Structural basis of Notch recognition by human γ-secretase. Nature. 2019 Jan;565(7738):192-197. Epub 2018 Dec 31 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

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A novel PSEN1 mutation in a patient with sporadic early-onset Alzheimer's disease and prominent cerebellar ataxia. J Alzheimers Dis. 2014;41(3):709-14. PubMed.

Other mutations at this position


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