Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PP2, BP4
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637563 C>T
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCA to CTA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4


This variant was found in a study that screened the APP, PSEN1, and PSEN2 genes in 1,431 Alzheimer’s disease (AD) patients from the Belgian neurology consortium BELNEU (Perrone et al., 2020). The authors used a targeted re-sequencing gene-panel and selected non-synonymous variants with a less than one percent minor allele frequency. The patient carrying this mutation also carried PSEN1 G183V. The two mutations segregated independently, as revealed by a sibling who carried G183V, but not P49L.

The double carrier was diagnosed with probable AD, which was later confirmed at autopsy. Onset of disease was late, past 65 years of age. The patient had memory impairment without other signs or symptoms. APOE genotype was E3/4.

P49L is not present in either the gnomAD or ExAC variant databases.

Neuropathology was consistent with AD, including robust neurofibrillary pathology. Of note, the brain lesions were different from those of the previously reported carrier of PSEN1 G183V, who had severe frontotemporal atrophy and Pick-like pathology (Dermaut et al., 2004). In the double carrier described here, there were no intranuclear neuronal inclusions and no signs of Pick’s disease, although a mild atrophy of the frontotemporal gyri was noted.

Brain imaging using SPECT showed moderate hypoperfusion of the bilateral parietal, temporal, and frontal lobes, compatible with AD, and MRI revealed age-related atrophy and multiple supratentorial lacunary infarcts.

Biological effect
As previously reported for the G183V mutation, the authors detected skipping of exon six, and rarely both exons six and seven, in lymphoblasts from the double-mutation carrier. However, these altered transcripts constituted less than 6 percent of total PSEN1 transcripts (20 percent when nonsense-mediated degradation was blocked), and were thus considered unlikely to interfere with the function of the wild-type protein. No splicing alterations were found near the P49L coding region.
Given the apparent minimal effects of G183V on transcript length and the patient’s AD neuropathology, the authors hypothesize that P49L could be the disease driver in this patient.

In silico algorithms to predict the effects of this variant on protein function (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) yielded conflicting results (Xiao et al., 2021), and its PHRED-scaled CADD score was below 20 (CADD v1.6, 2021).


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.


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 suggest no impact on 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 less than 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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Mutations Citations

  1. PSEN1 G183V

Paper Citations

  1. . Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108. PubMed.
  2. . A novel presenilin 1 mutation associated with Pick's disease but not beta-amyloid plaques. Ann Neurol. 2004 May;55(5):617-26. PubMed.
  3. . 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108. PubMed.

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