Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198085 C>T
Position: (GRCh37/hg19):Chr14:73664793 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCT to GTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was detected in a 50-year-old male with a four-year history of progressive memory impairment. He was diagnosed with Alzheimer’s disease based on clinical examination, MRI imaging, and CSF biomarkers, which showed a typical AD pattern (i.e., decreased Aβ42, increased total tau, increased phosphorylated tau). His affected father experienced onset at age 42 and died at 46 with advanced dementia and neuropathology consistent with AD. The patient’s paternal grandmother was also thought to have suffered from dementia in middle age (Luedecke et al., 2014).

In addition to the proband, the mutation was also detected in DNA retrieved from the archived brain of the proband's father. The mutation was absent in the patient’s unaffected mother, and therefore segregates with disease in this family. No other mutations were detected in PSEN1 or PSEN2, or in exons 16 or 17 of APP.

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

Neuropathology

Neuropathological examination of the proband's father revealed enlarged cerebral ventricles, atrophy of the frontal cortex, and the presence of neurofibrillary tangles and amyloid plaques consistent with a postmortem diagnosis of AD (Luedecke et al., 2014).

Biological Effect

Amyloid β production was disrupted in HEK293 cells expressing this variant (Schultz et al., 2023). While the Aβ42/Aβ40 ratio was increased, the ratio of short to long Aβ species was decreased, indicating a damaging effect. An indicator of γ-secretase function as a percentage of wildtype activity was developed combining the Aβ (37 + 38 + 40) / (42 + 43) ratio—a measure of γ-processivity—with the commonly used Aβ42/Aβ40 ratio—a measure of the relative production of aggregation-prone Aβ. This composite score, 48.17 for A275V, was strongly associated with AD age at onset, as well as biomarker and cognitive trajectories across multiple PSEN1 variants.

Consistent with these findings, an in vitro assay revealed an increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). In addition, 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).

The variant was classified as definetly pathogenic (Luedecke et al., 2014) according to the algorithm proposed by 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.

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.

PP1-M

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. A275V: At least one family with 2 affected carriers and >=1 unaffected noncarriers.

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: 17 Oct 2023

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References

Paper Citations

Luedecke D, Becktepe JS, Lehmbeck JT, Finckh U, Yamamoto R, Jahn H, Boelmans K. A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial Alzheimer disease. Neurosci Lett. 2014 Apr 30;566:115-9. Epub 2014 Feb 26 PubMed.
Schultz S, Liu L, Schultz A, Fitzpatrick C, Levin R, Bellier J-P, Shirzadi Z, Mathurin N, Chen C, Benzinger T, Day G, Farlow M, Gordon B, Hassenstab J, Jack C, Jucker M, Karch C, Lee J, Levin J, Perrin R, Schofield P, Xiong C, Johnson K, McDade E, Bateman R, Sperling R, Selkoe D, Chhatwal J, theDominantlyInheritedAlzheimer'sNetworkInvestigators. Functional variations in gamma-secretase activity are critical determinants of the clinical, biomarker, and cognitive progression of autosomal dominant Alzheimer's disease. 2023 Jul 25 10.1101/2023.07.04.547688 (version 2) bioRxiv.
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.
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.
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.

Mutations

PSEN1 A275V

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