Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227075815 G>A
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to ATA
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 7


This variant was found in a whole-exome sequencing screen for rare variants in genes associated with Alzheimer's disease (AD), frontotemporal dementia, and prion disease in a Dutch cohort of 68 patients with early onset AD (Wong et al., 2019).

The proband was a woman who started having symptoms at age 53. During the first three years of disease, she developed progressive anomia and memory loss. She was depressed and apathetic. Neurological examination two years after onset showed cognitive decline, short-term memory impairment, dyscalculia, bradyphrenia, and apraxia. She subsequently developed behavioral changes, including aggression, restlessness, obsessive thinking, blunted emotions, and binge eating.

The clinical diagnosis was either presenile AD with frontal presentation or a behavioral variant of frontotemporal dementia. After admission to a nursing home, she developed hallucinations, seizures, spasticity, and mutism. She died of pneumonia at 64. The patient’s mother had been diagnosed with AD at age 75.

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

Neuropathological examination of the proband was consistent with advanced stage AD with severe neuronal loss and gliosis of the frontal, temporal, occipital, and parietal cortices, as well as the hippocampus (Wong et al., 2019). Amyloid plaques and tau tangles were found in the neocortex, predominantly in the frontal cortex, and to a lesser extent in the parietal and temporal cortices and CA1 of the hippocampus. A small number of plaques were Aβ40-positive. In addition, Lewy bodies were found in the amygdala and parahippocampal cortex, and to a lesser extent in the substantia nigra and brainstem.

Biological Effect
The biological effect of this variant is unknown. Its PHRED-scaled CADD score, which integrates diverse information in silico, was slightly above 20, suggesting a deleterious effect (Wong et al., 2019). Wong and colleagues classified the variant as probably pathogenic using the Guerreiro et al., 2010 guidelines.


Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.


Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.


Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 22 Feb 2022


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Paper Citations

  1. . Genetic screening in early-onset Alzheimer's disease identified three novel presenilin mutations. Neurobiol Aging. 2019 Jan 29; PubMed.
  2. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Genetic screening in early-onset Alzheimer's disease identified three novel presenilin mutations. Neurobiol Aging. 2019 Jan 29; PubMed.

Other mutations at this position

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