Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3, BP5
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659443 C>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CAC to AAC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This PSEN1 mutation was originally identified in a Caucasian woman from Italy who met clinical criteria for probable Alzheimer’s disease (Piccoli et al., 2016). Her symptoms started at age 46 with executive dysfunction. She had a family history of dementia: Her maternal grandfather developed dementia at 50 years of age and died at 55. The proband’s mother presented with memory decline at age 55, and died at 62. Segregation with disease could not be determined.

A subsequent study identified the variant in a Korean man diagnosed with early onset AD using whole-exome sequencing (Bagyinszky et al., 2023). Of note, this carrier had additional rare variants in several genes associated with AD (including GRB2, ZCWPW1, TOMM40, NME8, RIN3, and DSG2), as well as in genes associated with other neurodegenerative conditions. The carrier’s symptoms emerged at age 38 and included deficits in attention and visuospatial function, short- and long-term memory loss, and impaired executive function. The proband’s father, paternal aunt, and paternal grandmother suffered from progressive cognitive decline with similar clinical phenotypes, although their ages at onset were in the early to mid-50s. Only the proband was genotyped so segregation with disease could not be determined.

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

Neuropathology

Neuropathological data are unavailable, but brain imaging and a blood test suggested pathology consistent with AD. A florbetaben-PET scan of the Korean carrier showed amyloid accumulation in lateral temporal-frontal-parietal areas, the posterior cingulate, and the precuneus (Bagyinszky et al., 2024). In addition, his levels of blood Aβ oligomerization, a candidate biomarker of AD, were consistent with the disease. MRI revealed mild hippocampal atrophy and moderate white matter hyperintensities in this individual. Moreover, a CT scan of the Italian carrier showed diffuse cerebral atrophy more pronounced in medial temporal lobes (Piccoli et al., 2016).

Biological Effect

A study that examined a range of Aβ peptides generated by this variant in human embryonic kidney cells lacking endogenous PSEN1 and PSEN2 and expressing this mutant revealed increased Aβ42/Aβ40 and decreased Aβ37/Aβ42, both indicators of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Of note, in this study, Aβ37/Aβ42 outperformed Aβ42/Aβ40 as a biomarker for distinguishing between control and AD samples.

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news). Moreover, structural modeling suggested the H214N substitution eliminates a hydrophobic interaction with PSEN1 W215, altering the stability and position of PSEN1’s transmembrane helix 4 in the plasma membrane (Bagyinszky et al., 2024).

H214 is evolutionarily conserved among vertebrates and several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) predicted it is damaging (Piccoli et al., 2016, Xiao et al., 2021, Bagyinszky et al., 2024).

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.

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. H214N: Variant is at edge of a mutational hot spot; 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.

BP5-P

Variant found in a case with an alternate molecular basis for disease. H214N: One of two affected carriers, also had several rare variants in genes associated with neurodegenerative diseases.

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Last Updated: 05 Mar 2024

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References

News Citations

Paper Citations

Piccoli E, Rossi G, Rossi T, Pelliccioni G, D'Amato I, Tagliavini F, Di Fede G. Novel PSEN1 mutations (H214N and R220P) associated with familial Alzheimer's disease identified by targeted exome sequencing. Neurobiol Aging. 2016 Apr;40:192.e7-11. Epub 2016 Feb 28 PubMed.
Bagyinszky E, Kim M, Park YH, An SS, Kim S. PSEN1 His214Asn Mutation in a Korean Patient with Familial EOAD and the Importance of Histidine-Tryptophan Interactions in TM-4 Stability. Int J Mol Sci. 2023 Dec 21;25(1) PubMed.
Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
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.
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 H214N

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