Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659443 C>T
dbSNP ID: rs63751003
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CAC to TAC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was detected in a French family (Alz 178) with at least five family members affected by early onset Alzheimer’s disease. Onset in this family occurred at 37 to 45 years of age. Inheritance was reported as autosomal dominant, but details of the segregation with disease were not reported (Raux et al., 2005).  

This mutation was later reported in an Iranian patient with a positive family history of dementia. The family, known as DEM12, had at least seven members affected by dementia, with a notably variable clinical phenotype. The proband developed symptom onset at the age of 51, starting with apathy and depression. Progressive memory impairment followed, along with disorientation to time and space, non-fluent aphasia, and myoclonic jerks. Five years after onset he was severely demented with visual hallucinations and stereotypic behavior. The clinical phenotype in this family was variable. The proband's mother was alive at the time of the report, living with frontotemporal dementia at the age of 81. The proband's aunt and two cousins were affected by Parkinson's disease with dementia, an uncle had dementia, and a grandfather had AD. Segregation of H214Y with disease could not be determined due to lack of DNA from family members (Lohmann et al., 2012).

This variant is found at a frequency of 0.000003976, with an allele count of only 1, in the gnomAD variant database (gnomAD v2.1.1, Sep 2021).

Neuropathology

Unknown. Imaging of the Iranian proband at age 52 showed global cortical atrophy with marked frontotemporal atrophy and white-matter lesions (Lohmann et al., 2012).

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).

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, Lohmann et al., 2012). It was classified as definitely pathogenic according to the algorithm proposed by Guerreiro et al., 2010 (Lohmann et al., 2012). 

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.

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References

News Citations

1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40? 20 Apr 2022
2. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019

Paper Citations

1. Raux G, Guyant-Maréchal L, Martin C, Bou J, Penet C, Brice A, Hannequin D, Frebourg T, Campion D. Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.
2. 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.
3. 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.
4. 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.
5. 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.
6. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

External Citations

1. gnomAD v2.1.1

Further Reading