Mutations

PSEN1 R269G

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Myoclonus
Position: (GRCh38/hg38):Chr14:73198066 C>G
Position: (GRCh37/hg19):Chr14:73664774 C>G
dbSNP ID: rs63751019
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGT to GGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in an individual with a family history of dementia (Perez-Tur et al., 1996). The proband’s father and uncle both died with dementia at 52 and 54 years of age, respectively, and anecdotal evidence suggests the grandfather also suffered from dementia. The proband’s first symptom, emerging at age 47, was memory loss. Other early symptoms included impaired speech fluency and seizures, although clinical evaluation was complicated by alcohol abuse.

The mutation was also found in a pair of siblings, both with an age of symptom onset of 49 years (Doran and Larner, 2004). One presented with depression, followed by obsessiveness and auditory hallucinations. Both individuals had agitation early in the disease, and both developed cognitive decline, seizures, and myoclonus. The mother, who was not genetically tested, developed AD at 79.

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

Neuropathology
Neuropathological data are unavailable. An MRI scan of one individual showed mild, non-specific cortical atrophy (Doran and Larner, 2004). In this same individual, EEG revealed a moderate, bilateral excess of slow wave activity, and SPECT imaging, 2.5 years after symptom onset, showed non-specific, moderate hypoperfusion of the posterior parietal cortex.

Biological Effect
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it decreases both Aβ40 and Aβ42 production, and increases the Aβ42/Aβ40 ratio (Sun et al., 2017).

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). These authors classified the variant as pathogenic using the ACMG-AMP guidelines (Richards et al., 2015).

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-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. R269G: Aβ42/Aβ40 ratio increased, but production of both peptides decreased.

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-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: 28 Feb 2022

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References

Paper Citations

  1. Perez-Tur J, Croxton R, Wright K, Phillips H, Zehr C, Crook R, Hutton M, Hardy J, Karran E, Roberts GW, Lancaster S, Haltia T. A further presenilin 1 mutation in the exon 8 cluster in familial Alzheimer's disease. Neurodegeneration. 1996 Sep;5(3):207-12. PubMed.
  2. Doran M, Larner AJ. Prominent behavioural and psychiatric symptoms in early-onset Alzheimer's disease in a sib pair with the presenilin-1 gene R269G mutation. Eur Arch Psychiatry Clin Neurosci. 2004 Jun;254(3):187-9. PubMed.
  3. 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.
  4. 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.
  5. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

Protein Diagram

Primary Papers

  1. Perez-Tur J, Croxton R, Wright K, Phillips H, Zehr C, Crook R, Hutton M, Hardy J, Karran E, Roberts GW, Lancaster S, Haltia T. A further presenilin 1 mutation in the exon 8 cluster in familial Alzheimer's disease. Neurodegeneration. 1996 Sep;5(3):207-12. PubMed.

Other mutations at this position

View Table

Alzpedia

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