Mutations

PSEN1 G209A

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192721 G>C
Position: (GRCh37/hg19):Chr14:73659429 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGA to GCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was first identified in a Korean woman with early onset Alzheimer’s disease (An et al., 2016). She presented with mild cognitive impairment and depression in her 40s. Her APOE genotype was E3/E3. Her mother had been diagnosed with an unspecified dementia, also in her 40s, and had died by age 60. The proband’s father and brother were unaffected. Segregation with disease could not be determined. One of the proband’s two daughters was a mutation carrier; she was asymptomatic in her 20s.

A Korean woman diagnosed with early onset AD and a family history of disease was subsequently reported as a carrier (Giau et al., 2019). Her symptoms began at age 54 and her APOE genotype was E3/E3. Of note, she also carried a rare variant in SPG11, a gene associated with spastic paraplegia type 11.

The mutation was also identified in a Japanese woman with AD onset at 48 years of age and an APOE3/3 genotype (Islam et al., 2022).

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

Neuropathology

Unknown. MRI showed global cortical atrophy, most prominent in the medial, temporal, and parietal lobes. FDG-PET revealed widespread bilateral hypometabolism, including in the temporal,  parietal, and frontal lobes.

Biological Effect

Unknown. 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, Giau et al. 2019). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment suggests mutations in G209 could alter the protein's local conformation and affect the positioning of residues that directly contribute to substrate binding (Zhou et al., 2019; Jan 2019 news).

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. G209A: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

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.

PM5-M

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

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

News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. An SS, Bagyinszky E, Kim HR, Seok JW, Shin HW, Bae S, Kim S, Youn YC. Novel PSEN1 G209A mutation in early-onset Alzheimer dementia supported by structural prediction. BMC Neurol. 2016 May 20;16:71. PubMed.
  2. 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.
  3. Islam S, Sun Y, Gao Y, Nakamura T, Noorani AA, Li T, Wong PC, Kimura N, Matsubara E, Kasuga K, Ikeuchi T, Tomita T, Zou K, Michikawa M. Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis. J Neurosci. 2022 Feb 23;42(8):1574-1586. Epub 2022 Jan 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. Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. An SS, Bagyinszky E, Kim HR, Seok JW, Shin HW, Bae S, Kim S, Youn YC. Novel PSEN1 G209A mutation in early-onset Alzheimer dementia supported by structural prediction. BMC Neurol. 2016 May 20;16:71. PubMed.

Other mutations at this position

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Alzpedia

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