Mutations

PSEN1 G417A

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Parkinsonism
Position: (GRCh38/hg38):Chr14:73219135 G>C
Position: (GRCh37/hg19):Chr14:73685843 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGT to GCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was found in a Korean man presenting with symptoms of AD and parkinsonism (Giau et al., 2018). Memory impairment started at age 34 and advanced rapidly with progressive language disturbance, visuo-spatial dysfunction, and behavioral changes. The patient also had a stooped posture, rigidity, and bradykinesia. None of his family members had reported similar symptoms. The mutation was absent from 662 unaffected individuals in the Korean Reference Genome Database, as well as from the ExAC and 1000 Genomes databases.

Neuropathology
Neuropathological data are unavailable, but MRI and PET scans were consistent with AD pathology. MRI revealed bilateral atrophy of parietal and anterior temporal regions, with diffuse cortical atrophy, and FDG-PET showed hypometabolism in the entire cortex, particularly in parietal areas. Moreover, a PiB-PET scan revealed widespread diffuse amyloid deposition, including the cerebellum, and the frontal, parietal, and temporal cortices.

Biological Effect
The biological effect of this mutation is unknown, but it is in a conserved site and multiple in silico analysis tools (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Revee) predicted this variant is damaging (Giau et al., 2018, Xiao et al., 2021). Moreover, ExPASy algorithms indicated significant changes in bulkiness, polarity, and hydrophobicity. The authors noted this may result in reduced flexibility within the helix of transmembrane domain-VIII, a hypothesis supported by 3D structural modeling. Additionally, the mutation may impair splicing, as it is near a known acceptor and a potential donor splice sites.

Pathogenicity

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.

PM1-M

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

PM2-M

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.

PP2-P

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

PP3-M

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. G417A: CADD score and structural modeling support a deleterious effect.

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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References

Paper Citations

  1. Giau VV, Wang MJ, Bagyinszky E, Youn YC, An SS, Kim S. Novel PSEN1 p.Gly417Ala mutation in a Korean patient with early-onset Alzheimer's disease with parkinsonism. Neurobiol Aging. 2018 Dec;72:188.e13-188.e17. Epub 2018 Aug 9 PubMed.
  2. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. 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

Papers

  1. Giau VV, Bagyinszky E, Yang YS, Youn YC, An SS, Kim SY. Genetic analyses of early-onset Alzheimer's disease using next generation sequencing. Sci Rep. 2019 Jun 10;9(1):8368. PubMed.

Protein Diagram

Primary Papers

  1. Giau VV, Wang MJ, Bagyinszky E, Youn YC, An SS, Kim S. Novel PSEN1 p.Gly417Ala mutation in a Korean patient with early-onset Alzheimer's disease with parkinsonism. Neurobiol Aging. 2018 Dec;72:188.e13-188.e17. Epub 2018 Aug 9 PubMed.

Other mutations at this position

View Table

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