Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Corticobasal Syndrome
Position: (GRCh38/hg38):Chr14:73198110 T>G
Position: (GRCh37/hg19):Chr14:73664818 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTT to TTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in a screen for APP and PSEN1 mutations in individuals with autosomal-dominant familial AD seen at the Dementia Research Centre in London, U.K. (Scahill et al., 2013; Ryan et al., 2016). The mutation was present in three affected members of a family that included 15 affected individuals with mean age at onset of 46 years. All mutation cases had an amnestic presentation. The mutation was absent from two unaffected family members and 100 healthy controls.

The mutation was also found in two members of a Canadian family who were diagnosed with having probable corticobasal syndrome (Lam et al., 2017). The age at onset for these patients was 48 and 51 years, with a disease duration of 10 and six years, respectively. Initial symptoms included inattention, dysexecutive syndrome, and depressed mood. In one case, the patient also had memory impairment and personality changes. The mutation was not found in several genetic variant databases, including ExAC, 1000 Genomes, and the Exome Variant Server.

Neuropathology
Neuropathology consistent with AD was reported in two affected individuals from the family with three identified mutation carriers (Ryan et al., 2016). Similarly, the brains of the Canadian mutation carriers revealed typical AD neuropathology, including amyloid angiopathy and neuritic plaques, as well as neurofibrillary tangles in the frontal, temporal, and parietal cortices, despite their corticobasal syndrome diagnoses (Lam et al., 2017). There were no signs of FTLD-tau nor TDP-43 pathology, and only rare α-synuclein- positive Lewy bodies in the amygdala of one case. MRI showed severe parietal, perirolandic, and temporal atrophy with relative sparing of frontal and ipsilateral hippocampal regions. SPECT revealed hypoperfusion of brain regions contralateral to the patients' affected limbs; in one case, specifically temporal and parietal regions.

Biological Effect
The mutation is predicted to have a damaging effect according to in silico analyses SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve (Ryan et al., 2016; Lam et al., 2017, Xiao et al., 2021). It is conserved between species.

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.

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-S

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. F283L: At least one family with >=3 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: 22 Feb 2022

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References

Paper Citations

Scahill RI, Ridgway GR, Bartlett JW, Barnes J, Ryan NS, Mead S, Beck J, Clarkson MJ, Crutch SJ, Schott JM, Ourselin S, Warren JD, Hardy J, Rossor MN, Fox NC. Genetic Influences on Atrophy Patterns in Familial Alzheimer's Disease: A Comparison of APP and PSEN1 Mutations. J Alzheimers Dis. 2013 Jan 1;35(1):199-212. PubMed.
Ryan NS, Nicholas JM, Weston PS, Liang Y, Lashley T, Guerreiro R, Adamson G, Kenny J, Beck J, Chavez-Gutierrez L, de Strooper B, Revesz T, Holton J, Mead S, Rossor MN, Fox NC. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. Epub 2016 Oct 21 PubMed.
Lam B, Khan A, Keith J, Rogaeva E, Bilbao J, St George-Hyslop P, Ghani M, Freedman M, Stuss DT, Chow T, Black SE, Masellis M. Characterizing familial corticobasal syndrome due to Alzheimer's disease pathology and PSEN1 mutations. Alzheimers Dement. 2016 Oct 12; 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 F283L

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