Pathogenicity: Alzheimer's Disease : Uncertain Significance
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659469 G>C
dbSNP ID: rs63751072
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CAG to CAC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7


This mutation was found in an Australian woman diagnosed with dementia at 35 years of age (Miklossy et al., 2003). She subsequently developed seizures, aphasia, decreasing mobility, and swallowing difficulties. Three family members also developed dementia in their late 30s or early 40s. The proband’s daughter was found to carry the mutation, but was asymptomatic at age 30.

The variant was also described in a case of sporadic AD with spastic paraparesis in a French study (Lanoiselee et al., 2017). The mutation carrier had an age at onset of 46 years and disease duration of 4 years.

The mutation was absent from 100 unrelated Australian controls (Miklossy et al., 2003) and from the gnomAD variant database (gnomAD v2.1.1, July 2021).


In the Australian carrier, neuropathology was consistent with AD (Miklossy et al., 2003). Aβ42 but not Aβ40, was detectable by immunoblot and ELISA in frontal cortex homogenates. In the French carrier, AD biomarkers in cerebrospinal fluid, including Aβ42, tau, and phospho-tau, were consistent with AD (Lanoiselee et al., 2017). Brain imaging in this patient revealed diffuse cortical atrophy with moderate leukopathy, diffuse microbleeds, and bilateral hypoperfusion predominant in the right frontal and temporal cortices (Lacour et al., 2019). 

Biological Effect

Unknown, but 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. . 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. . APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
  3. . Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer's Disease Before 51 Years. J Alzheimers Dis. 2019;71(1):227-243. 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


  1. . Redox proteomics identification of oxidatively modified brain proteins in inherited Alzheimer's disease: an initial assessment. J Alzheimers Dis. 2006 Dec;10(4):391-7. PubMed.

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.

Other mutations at this position


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