Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192646 A>G
Position: (GRCh37/hg19):Chr14:73659354 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Missense
Codon Change: GAA to GGA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was found in a large French study reporting 56 new families with autosomal-dominant early onset Alzheimer's disease. All probands met NINCDS-ADRDA criteria for probable AD and had a family history of disease (Wallon et al., 2012).

The E184G mutation was initially identified in two families, ALZ 013 and EXT 134. The ALZ 013 family had two confirmed mutation carriers and eight affected family members. The age of onset in this family ranged from 43 to 52 years, and disease duration ranged from five to 14 years. The mutation appears to segregate with disease in this family. The EXT 134 family had two mutation carriers and three affected family members. In this family symptoms started at age 51 or 52, with a duration of seven to eight years. Segregation with disease could not be definitively determined. An unspecified number of mutation carriers developed symptoms consistent with a frontal variant of AD and were affected by early myoclonic epilepsy. In a subsequent study, seizures were reported in two of three French mutation carriers with average age at onset of 44.5 years (Zarea et al. 2016). The average time between AD onset and first seizure was eight years.

The mutation was also found in in a 41-year-old Thai woman with memory loss and a family history of dementia (Giau et al., 2019, Senanarong et al., 2020). The father and grandfather of the patient were diagnosed with dementia. In the patient, no additional mutations were found in 50 genes related to neurodegenerative disease. The mutation was absent from several variant databases, including KRGDB, ExAC, and 1000Genomes.

Neuropathology

Although neuropathological data are unavailable, MRI in one patient revealed global cortical atrophy (Senanarong et al., 2020).

Biological Effect

An in vitro assay using purified proteins to test this mutant's ability to cleave the APP-C99 substrate revealed it generates less Aβ42, and particularly less Aβ40, than wild-type PSEN1, resulting in an approximately five-fold elevation of the Aβ42/Aβ40 ratio (Sun et al., 2017). Moreover, the mutation may disturb splicing near exon 7 (Giau et al., 2019). Three pathogenicity-predicting algorithms--PolyPhen2, Sift, and Provean--classified the mutation as damaging. In addition, 3-D modeling predicted structural changes, possibly including increased flexibility of PSEN1's third transmembrane helix, as well as disruption of inter- and/or intra-helical interactions (Senanarong et al., 2020).

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-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. E184G: Aβ42/Aβ40 ratio increased, but production of both peptides decreased.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. E184G: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.

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: 10 Nov 2022

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References

Paper Citations

Wallon D, Rousseau S, Rovelet-Lecrux A, Quillard-Muraine M, Guyant-Maréchal L, Martinaud O, Pariente J, Puel M, Rollin-Sillaire A, Pasquier F, Le Ber I, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Thomas-Antérion C, Paquet C, Moreaud O, Gabelle A, Sellal F, Sauvée M, Laquerrière A, Duyckaerts C, Delisle MB, Streichenberger N, Lannes B, Frebourg T, Hannequin D, Campion D. The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. PubMed.
Zarea A, Charbonnier C, Rovelet-Lecrux A, Nicolas G, Rousseau S, Borden A, Pariente J, Le Ber I, Pasquier F, Formaglio M, Martinaud O, Rollin-Sillaire A, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Ceccaldi M, Gabelle A, Chamard L, Blanc F, Sellal F, Paquet C, Campion D, Hannequin D, Wallon D, PHRC GMAJ Collaborators. Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.
Giau VV, Senanarong V, Bagyinszky E, An SS, Kim S. Analysis of 50 Neurodegenerative Genes in Clinically Diagnosed Early-Onset Alzheimer's Disease. Int J Mol Sci. 2019 Mar 26;20(6) PubMed.
Senanarong V, An SS, Vo Van G, Limwongse C, Bagyinszky E, Kim S. Pathogenic PSEN1 Glu184Gly Mutation in a Family from Thailand with Probable Autosomal Dominant Early Onset Alzheimer's Disease. Diagnostics (Basel). 2020 Mar 1;10(3) 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.
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.

Mutations

PSEN1 E184G

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