Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73186901 T>G
Position: (GRCh37/hg19):Chr14:73653609 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTT to GTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was first identified in a screen of 148 Chinese individuals diagnosed with familial Alzheimer’s disease (Gao et al., 2019). The search focused on the APP, PSEN1, and PSEN2 genes, including exons 3-12 of PSEN1. The carrier of F177V was a woman with age at onset of 45 years. At 50, her symptoms included memory impairment, executive dysfunction, disorientation, dyscalculia, and disrupted visuospatial skills. Her APOE genotype was E3/E4.

A subsequent study reported co-segregation of the mutation with AD in a Chinese family spanning three generations with a mean age at onset of 39 years (Jiang et al., 2020). The mutation was present in five affected family members and absent from three healthy members, as well as from the gnomAD variant database. Two affected siblings presented with memory deficits as their first symptom and one of them went on to develop neuropsychiatric symptoms, including depression and anxiety. Another three affected members initially presented with anxiety and/or behavioral changes. One of these individuals gradually developed memory deficits, but the other two showed no signs of memory impairment one to two years later.

Neuropathology
Neuropathological data are unavailable, but an MRI scan of one patient revealed global brain atrophy, especially in the temporal region and hippocampus (Jiang et al., 2020).

Biological Effect
In cell transfection studies using neuroblastoma cells over-expressing APP751, the mutant protein increased both the production of Aβ42 and the ratio of Aβ42 over Aβ40, as compared with wild-type PSEN1 (Jiang et al., 2020).

The substitution of a phenylalanine with a valine is expected to decrease interactions with other hydrophobic residues, possibly affecting protein structure (Gao et al., 2019). Cryo-electron microscopy studies of the atomic structure of γ-secretase bound to Notch or APP fragments indicate F177 directly interacts with residues from Notch, but not APP (Zhou et al., 2019; Yang et al., 2019; Jan 2019 news). Two other mutations at this site, F177L and F177S, have been reported in individuals with a strong family history of AD. In silico analyses, including PolyPhen, SIFT, MutationTaster, and CADD (28.3), predicted the mutation is damaging (Gao et al., 2019; Jiang et al., 2020). Also, orthologous sequence alignments revealed F177 is an evolutionarily conserved residue.

The mutation was first classified as probably pathogenic (Gao et al., 2019) and subsequently as pathogenic (Jiang et al., 2020) based on ACMG standards (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.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

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. F177V: 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

News Citations

Mutations Citations

Paper Citations

Gao Y, Ren RJ, Zhong ZL, Dammer E, Zhao QH, Shan S, Zhou Z, Li X, Zhang YQ, Cui HL, Hu YB, Chen SD, Chen JJ, Guo QH, Wang G. Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease. Neurobiol Aging. 2019 May;77:154-157. Epub 2019 Jan 31 PubMed.
Jiang B, Bi M, Li J, Liu Q, Xiao NA, Fang J, Shi MY, Yu ZW, Ma QL, Tong SJ, Zheng KM. A Pathogenic Variant p.Phe177Val in PSEN1 Causes Early-Onset Alzheimer's Disease in a Chinese Family. Front Genet. 2020;11:713. Epub 2020 Jul 10 PubMed.
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.
Yang G, Zhou R, Zhou Q, Guo X, Yan C, Ke M, Lei J, Shi Y. Structural basis of Notch recognition by human γ-secretase. Nature. 2019 Jan;565(7738):192-197. Epub 2018 Dec 31 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 F177V

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