Mutations
PSEN1 G217R
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Overview
Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity
Criteria: PS3, PM2, PP2, PP3
Clinical
Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192744 G>C
Position: (GRCh37/hg19):Chr14:73659452 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA
Change: Substitution
Expected RNA
Consequence: Substitution
Expected Protein
Consequence: Missense
Codon
Change: GGT to CGT
Reference
Isoform: PSEN1 Isoform 1 (467 aa)
Genomic
Region: Exon 7
Findings
This mutation was first identified in a woman with a strong family history of early onset AD (Norton et al., 2009). The family included eight affected members, spanning four generations, with a mean age at onset of 45.5 years and a mean age at death of 55.5 years. In addition to the proband, a first-degree cousin was also found to carry the mutation. The clinical progression of the disease of the cousin's son was reported. At age 44, he had anxiety attacks and depression, and by 46, memory loss and disorientation prevented him from doing his delivery job. At age 51, he developed incontinence and confusion, and went through several hospitalizations for agitation and aggressive behavior. He died at age 52.
This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).
Neuropathology
At autopsy, the brain of the patient who was clinically followed, revealed neuropathology typical of AD with mild generalized atrophy. In addition, a large number of cotton-wool plaques was observed.
Biological Effect
Several studies have shown that this variant disrupts APP processing. In neurons generated from induced pluripotent stem cells (iPSCs) derived from a carrier, the Aβ42/Aβ40 ratio was increased and the Aβ37/Aβ42 decreased, indicating reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Moreover, in HEK293 cells transiently cotransfected with a human APP cDNA and a PSEN1 cDNA construct carrying the G217R mutation, the secreted Aβ42/Aβ40 ratio was elevated approximately three-fold compared with that of control cells expressing a wild-type PSEN1 construct (Norton et al., 2009). Also, an in vitro assay using purified proteins to test the mutant’s ability to cleave the APP-C99 substrate revealed an increase in the Aβ42/Aβ40 ratio (Sun et al., 2017).
Of note, while the study in iPSC-derived neurons revealed an increase in Aβ40 and Aβ42 levels, the in vitro study showed the opposite. This may reflect a limitation of the in vitro assay—nearly half of all 138 mutant PSEN1 enzymes tested produced less than 10 percent of the Aβ40 and Aβ42 produced by the wildtype protein (Liu et al., 2021).
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).
Pathogenicity
Alzheimer's Disease : Likely Pathogenic
This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.
PS3-S
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
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-P
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: 17 Nov 2022
References
News Citations
Paper Citations
- Norton JB, Cairns NJ, Chakraverty S, Wang J, Levitch D, Galvin JE, Goate A. Presenilin1 G217R mutation linked to Alzheimer disease with cotton wool plaques. Neurology. 2009 Aug 11;73(6):480-2. PubMed.
- Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
- Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
- Liu L, Lauro BM, Wolfe MS, Selkoe DJ. Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
- 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.
External Citations
Further Reading
No Available Further Reading
Protein Diagram
Primary Papers
- Norton JB, Cairns NJ, Chakraverty S, Wang J, Levitch D, Galvin JE, Goate A. Presenilin1 G217R mutation linked to Alzheimer disease with cotton wool plaques. Neurology. 2009 Aug 11;73(6):480-2. PubMed.
Other mutations at this position
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