Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, PSP/CBS
Reference Assembly: GRCh37/hg19
Position: Chr14:73637680 C>G
dbSNP ID: rs1897874329
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCT to CGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4


This variant was identified in a woman of Moroccan ancestry suffering from symptoms reminiscent of progressive supranuclear palsy (Thomas et al., 2022). Symptoms included parkinsonism with difficulty initiating movement and rigidity, foot dystonia, spastic paraparesis, postural instability, frontal dementia, and supranuclear gaze palsy. Her first symptoms, abnormal gait and rapid weight loss, emerged at age 51 and by 54 she was wheelchair-bound. She subsequently developed epileptic seizures and died at age 55. Her mother had developed similar symptoms and also died before age 60, and her son had psychiatric problems.

Despite her PSP-like clinical phenotype, the patient was diagnosed with “PSEN1-associated Alzheimer’s disease” because singleton exome sequencing revealed she carried the PSEN1 P88R variant, and she had cerebrospinal fluid and brain imaging biomarkers of AD (see below).

This variant was absent from the ExAC and gnomAD variant databases.

Neuropathological data are unavailable, but an MRI brain scan of the proband revealed bilateral temporal and parietal atrophy with abundant white matter hyperintensities (Thomas et al., 2022). In addition, cerebrospinal fluid levels of Aβ42 and the Aβ42/Aβ40 ratio were reduced, as occurs in AD, although total tau and phosphorylated tau levels were normal. Brain imaging of dopamine transporters (DAT) showed no signs of dopaminergic denervation.

Biological Effect
The biological effect of this variant is unknown, but several in silico algorithms, including CADD (PHRED-scaled score = 32), predicted it is deleterious (Thomas et al., 2022).  Moreover, the variant is at a position where a pathogenic variant was previously reported and the amino acid is highly conserved.


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.


Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.


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.


Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.


Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.


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 Apr 2022


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Paper Citations

  1. . A New Presenilin-1 Missense Variant Associated With a Progressive Supranuclear Palsy-like Phenotype. Alzheimer Dis Assoc Disord. 2022 Mar 30; PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A New Presenilin-1 Missense Variant Associated With a Progressive Supranuclear Palsy-like Phenotype. Alzheimer Dis Assoc Disord. 2022 Mar 30; PubMed.

Other mutations at this position

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