Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73664819 C>T
dbSNP ID: rs63750324
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CCA to TCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8


This mutation was found in four members of a family in whom affected members presented with dementia, spastic paraparesis, and white-matter lesions (Marrosu et al., 2006). Memory impairment and personality changes characterized the onset of disease, which ranged between 32 and 45 years of age. In addition, motor impairments, including spastic paraparesis, emerged early on. All mutation carriers had an APOE 3/3 genotype. The mutation was absent from 96 patients with sporadic multiple sclerosis and 96 unrelated, healthy controls. It was also absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).


Neuropathological data are unavailable. However, MRI scans from four individuals revealed disseminated white-matter lesions reminiscent of those found in multiple sclerosis (Marrosu et al., 2006). Areas of hyperintensity in the frontal and temporal lobes were similar to those seen in cerebral autosomal-dominant arteriopathy (CADASIL), but no subcortical lacunar lesions typical of CADASIL were observed. Two subjects demonstrated multiple microbleeds in lobar regions (Floris et al., 2015).

Biological Effect

In an in vitro assay using the APP-C99 substrate, the mutant protein produced Aβ40 and Aβ42 peptides at levels similar to those generated by wild-type PSEN1. Accordingly, the Aβ42/Aβ40 ratio was similar to controls (Sun et al., 2017).

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: 13 Sep 2021


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Paper Citations

  1. . Dementia, pyramidal system involvement, and leukoencephalopathy with a presenilin 1 mutation. Neurology. 2006 Jan 10;66(1):108-11. PubMed.
  2. . Multiple Spontaneous Cerebral Microbleeds and Leukoencephalopathy in PSEN1-Associated Familial Alzheimer's Disease: Mirror of Cerebral Amyloid Angiopathy?. J Alzheimers Dis. 2015;47(3):535-8. PubMed.
  3. . 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.
  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. . Dementia, pyramidal system involvement, and leukoencephalopathy with a presenilin 1 mutation. Neurology. 2006 Jan 10;66(1):108-11. PubMed.

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