Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640295 A>T
dbSNP ID: rs63751272
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAA to GAT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was first identified in two Israeli siblings with a family history of early onset Alzheimer’s disease accompanied by seizures. The reported pedigree included four affected individuals over three generations. The proband experienced onset of progressive memory impairment and disorientation at age 48. His father died at age 55 with similar symptoms. The proband’s two siblings, a sister and a brother, experienced progressive cognitive dysfunction at ages 43 and 46 years respectively, and developed epileptic seizures within 18 months of symptom onset (Reznik-Wolf et al., 1996).

In a paper investigating patterns of pathology associated with various familial AD mutations, two brain specimens from patients carrying E120D mutations were analyzed, but it was not indicated whether these individuals carried the A>T or A>C transversion. Age of onset in these individuals was recorded as 34 and 53 and age at death as 51 and 62 years, respectively. Language loss, seizures, and rigidity were noted as clinical features (Mann et al., 2001).

The variant was absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).

Neuropathology

Unknown.

Biological Effect

This mutant appears to reduce γ-processivity (Liu et al., 2021). Analysis of secreted Aβs in the conditioned media of human embryonic kidney cells lacking endogenous PSENs and expressing this mutant (nucleotide change unspecified) along with wildtype APP, revealed increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios. Secreted levels of total Aβ were reduced. Interestingly, the authors also reported that Aβ42/40, Aβ38/42, and particularly Aβ37/42, ratios each correlated with reported ages of onset of clinical impairment across 16 PSEN1 mutations, including E120D.

Consistent with these findings, an in vitro assay using purified proteins to test the ability of an E120D mutant (nucleotide change unspecified) to cleave the APP-C99 substrate revealed decreased Aβ42, and particularly Aβ40, production resulting in a greater than 5-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017).

Although one study reported mixed results using multiple in silico algorithms to predict the effects of this variant on protein function (Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).

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.

PS1-S

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

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.

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: 22 Feb 2022

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References

Paper Citations

Reznik-Wolf H, Treves TA, Davidson M, Aharon-Peretz J, St George Hyslop PH, Chapman J, Korczyn AD, Goldman B, Friedman E. A novel mutation of presenilin 1 in familial Alzheimer's disease in Israel detected by denaturing gradient gel electrophoresis. Hum Genet. 1996 Dec;98(6):700-2. PubMed.
Mann DM, Pickering-Brown SM, Takeuchi A, Iwatsubo T, . Amyloid angiopathy and variability in amyloid beta deposition is determined by mutation position in presenilin-1-linked Alzheimer's disease. Am J Pathol. 2001 Jun;158(6):2165-75. 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.
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 E120D (A>T)

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