Mutations
PSEN1 W165C (G>C)
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Overview
Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity
Criteria: PS1, PM1, PM2, PP2, PP3
Clinical
Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73653575 G>C
dbSNP ID: rs63751484
Coding/Non-Coding: Coding
DNA
Change: Substitution
Expected RNA
Consequence: Substitution
Expected Protein
Consequence: Missense
Codon
Change: TGG to TGC
Reference
Isoform: PSEN1 Isoform 1 (467 aa)
Genomic
Region: Exon 6
Findings
This mutation was initially detected in a French kindred (Alz 064) reported to have three individuals affected by AD, spanning three generations (Campion et al., 1999). Age at onset ranged from 37 to 47 years. The proband was homozygous for the APOE3 allele.
The variant was also found in a Chinese man with a family history of AD and age at onset of 47 years (Mao et al., 2021). His APOE genotype was E2/E3.
This variant was absent from the gnomAD variant database (gnomAD v2.1.1, June 2021).
Neuropathology
Unknown
Biological Effect
Although the biological effect of this mutation is unknown, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, W165 is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news). Moreover, three in silico algorithms (SIFT, Polyphen2, and LRT) predicted the W165C is deleterious (Mao et al., 2021) and three-dimensional modeling of a synonymous substitution, W165C (G>T), suggested it induces significant conformational changes (Van Giau et al., 2019).
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.
PS1-S
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
PM1-S
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. W165C (G>C): Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.
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.
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
References
News Citations
Mutations Citations
Paper Citations
- Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
- Mao C, Li J, Dong L, Huang X, Lei D, Wang J, Chu S, Liu C, Peng B, Román GC, Cui L, Gao J. Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort. Curr Alzheimer Res. 2021;18(3):265-272. 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.
- Van Giau V, Pyun JM, Suh J, Bagyinszky E, An SS, Kim SY. A pathogenic PSEN1 Trp165Cys mutation associated with early-onset Alzheimer's disease. BMC Neurol. 2019 Aug 7;19(1):188. PubMed.
External Citations
Further Reading
No Available Further Reading
Protein Diagram
Primary Papers
- Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
Other mutations at this position
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