Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73217182 G>A
Position: (GRCh37/hg19):Chr14:73683890 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCC to ACC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation was first detected in a man of mixed Turkish and Bulgarian ancestry. He developed symptoms of Alzheimer’s disease, starting with apathy and behavioral disturbances affecting activities of daily living, at the age of 43. He developed significant cognitive decline along with intermittent visual hallucinations.

At least three additional members of this family (AD-46) were affected by dementia. The proband’s mother and maternal aunt had died with dementia in their 60s (onset at age 35 and 56, respectively). The proband’s maternal grandmother was also affected and died at age 70 (Lohmann et al., 2012).

The mutation was also found in a family spanning three generations with early-onset AD from the Dominantly Inherited Alzheimer Network (DIAN) Extended Registry (Hsu et al., 2018). The proband and the proband’s parent had ages at symptomatic onset of 50 and 57 years, respectively. In the parent, AD was confirmed at autopsy at age 67 years. The mutation was absent in two population-based exome sequencing databases, EVS and ExAC.

The mutation was also reported in a man diagnosed with AD whose cognitive impairment first manifested at 56 years of age and who died at 67 (Gondim et al., 2019).

Neuropathology

Neuropathology in one case was consistent with AD, including widespread tau and Aβ pathologies, but also included widespread α-synuclein inclusions, suggesting diffuse Lewy body disease (Gondim et al., 2019). Tau and α-synuclein aggregates were found co-existing in the same neuron. MRI brain scans of another case showed atrophy of the frontal lobes (Lohmann et al., 2012).

Biological Effect

Mouse neuroblastoma cells expressing PSEN1 A396T produced significantly more Aβ42 and Aβ40 than cells expressing wild-type PSEN1, with the Aβ42/Aβ40 ratio remaining unchanged (Hsu et al., 2018; Hsu et al., 2020). In an in vitro assay using isolated proteins, Aβ42 production was similar to that of the wild-type protein, but Aβ40 production was reduced, resulting in an approximately two-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) predicted this variant is damaging (Xiao et al., 2021, Hsu et al., 2018; Hsu et al., 2020). Hsu and colleagues classified the variant as probably pathogenic (Hsu et al., 2020)

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-P

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. A396T: Although one assay showed an increased Aβ42/Aβ40 ratio, other observations were inconsistent.

PM1-P

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. A396T: Variant located at edge of mutational hot spot.

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: 22 Feb 2022

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References

Paper Citations

Lohmann E, Guerreiro RJ, Erginel-Unaltuna N, Gurunlian N, Bilgic B, Gurvit H, Hanagasi HA, Luu N, Emre M, Singleton A. Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
Hsu S, Gordon BA, Hornbeck R, Norton JB, Levitch D, Louden A, Ziegemeier E, Laforce R Jr, Chhatwal J, Day GS, McDade E, Morris JC, Fagan AM, Benzinger TL, Goate AM, Cruchaga C, Bateman RJ, Dominantly Inherited Alzheimer Network (DIAN), Karch CM. Discovery and validation of autosomal dominant Alzheimer's disease mutations. Alzheimers Res Ther. 2018 Jul 18;10(1):67. PubMed.
Gondim DD, Oblak A, Murrell JR, Richardson R, Epperson F, Ross OA, Ghetti B. Diffuse Lewy Body Disease and Alzheimer Disease: Neuropathologic Phenotype Associated With the PSEN1 p.A396T Mutation. J Neuropathol Exp Neurol. 2019 Jul 1;78(7):585-594. PubMed.
Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 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 A396T

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