Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173651 G>T
Position: (GRCh37/hg19):Chr14:73640359 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTC to TTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was identified in an Iranian family with early onset Alzheimer’s disease (Wang et al., 2018). The mother and four of her six offspring were affected, with ages of onset ranging from 35 to 42 years. Early symptoms included deficits in recent episodic memory and visuospatial perception. These symptoms were followed by deterioration of working memory and executive function, word-finding difficulties, and behavioral changes, including apathy, depression, agitation, aggression, and sleep disorders. Myoclonic jerks were present in all affected individuals at advanced stages of disease. The mother and three of the four affected siblings died within seven years of symptom onset.

DNA samples were available from one affected individual and two of his unaffected siblings. The patient was found to carry a novel mutation in PSEN1 that resulted in a valine-to-phenylalanine substitution at amino acid 142; no other pathogenic mutations were found in APP, PSEN1, or PSEN2 in this individual. The PSEN1 V142F mutation was absent in the two unaffected siblings, in 87 neurologically healthy Iranian controls, and in the gnomAD variant database (gnomAD v2.1.1, May 2021).

Neuropathology

Neuropathological information is not available. However, MRI of one family member during the late stage of disease revealed severe, global cortical atrophy, which was most pronounced in frontal and temporal lobes.

Biological Effect

Several in silico algorithms (MutPred, SNP&Go, SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Wang et al., 2017; Xiao et al., 2021).

Valine-142, located in the second transmembrane domain, is conserved across species and in presenilin-2. This residue is located near several other pathogenic PSEN1 mutations aligned along the helical face, supporting the pathogenicity of this mutation (Guerreiro et al., 2010; Wang et al., 2018).

Pathogenicity

Alzheimer's Disease : Likely Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

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-P

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.

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

Wang JC, Alinaghi S, Tafakhori A, Sikora E, Azcona LJ, Karkheiran S, Goate A, Paisán-Ruiz C, Darvish H. Genetic screening in two Iranian families with early-onset Alzheimer's disease identified a novel PSEN1 mutation. Neurobiol Aging. 2018 Feb;62:244.e15-244.e17. Epub 2017 Oct 23 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.

Mutations

PSEN1 V142F

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