Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Parkinsonism, Subcortical Dementia
Position: (GRCh38/hg38):Chr14:73198076 T>C
Position: (GRCh37/hg19):Chr14:73664784 T>C
dbSNP ID: rs63750680
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTT to GCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was first identified in two members of a Spanish family with four affected individuals, spanning three generations, with early onset subcortical dementia and parkinsonism (Jimenez-Escrig et al., 2004). The age of onset ranged from 26 to 36 years old. The proband developed dementia characterized by forgetfulness, slowness of thought, impaired ability to manipulate acquired knowledge, as well as apathy and depression, fulfilling the criteria for subcortical dementia. The initial symptom of the other mutation carrier, the proband’s sister, was attention deficit.  Medical records from the proband’s mother indicated her main symptoms were depression and parkinsonism, and family accounts revealed the grandmother suffered for several years from cognitive decline before dying in her 40s.

The mutation was also found in a screening for variants in coding regions of the PSEN1, PSEN2, and APP genes in 231 Iberian patients with a clinical diagnosis of early onset AD (Guerreiro et al., 2010). In this case, the proband presented with myoclonus and dementia beginning at 34 years of age. The father and three siblings who carried the mutation also developed dementia. The mutation was absent from 121 age-matched Iberian controls,130 individuals from seven different African populations, and from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology
Neuropathology in the original proband was typical of AD, but also included Lewy bodies in the cortex and substantia nigra, and widespread subcortical neuritic lesions (Jimenez-Escrig et al., 2004). In addition, MRI and PET imaging revealed abnormalities only in the later stages of disease, most prominently in subcortical-frontal areas. This is in contrast to the classic AD profile with early hypometabolism in temporal and parietal cortices. 

Biological Effect
Elevated levels of Aβ42 peptide were detected in the plasma of two patients (Jimenez-Escrig et al., 2004). Moreover, an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate indicated it boosts Aβ42 production, resulting in an approximately fivefold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). The V272 position is conserved between PSEN1 and PSEN2, but is not in a transmembrane domain. 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). It has been classified as definitely pathogenic (Guerreiro et al., 2010) and as pathogenic (Xiao et al., 2021) using the ACMG-AMP guidelines (Richards et al., 2015).

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

Paper Citations

1. Jimenez-Escrig A, Rabano A, Guerrero C, Simon J, Barquero MS, Güell I, Ginestal RC, Montero T, Orensanz L. New V272A presenilin 1 mutation with very early onset subcortical dementia and parkinsonism. Eur J Neurol. 2004 Oct;11(10):663-9. PubMed.
2. 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.
3. 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.
4. 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.
5. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

External Citations

1. gnomAD v2.1.1,

Further Reading

Learn More

1. Japanese Familial Alzheimer's Disease Database