Mutations
PSEN1 F176V
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Overview
Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity
Criteria: PS3, PM1, PM2, PP2, BP4
Clinical
Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73186898 T>G
Position: (GRCh37/hg19):Chr14:73653606 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 variant was identified in a woman in the U.S. who developed memory impairment at age 59 and continued to cognitively deteriorate until her death at age 77 (Ghetti et al., 2014). She was initially diagnosed as being in the early stages of Alzheimer’s disease, but neuropathology was somewhat atypical (see below). Members of her family spanning three generations had suffered from presenile dementia.
Neuropathology
At autopsy, neuropathological examination of the proband revealed moderate-to-severe atrophy of the head of the caudate nucleus and severe atrophy of the hippocampus and parahippocampal cortex (Ghetti al., 2014). In addition, Aβ plaques, tau-immunopositive neurons, and neuropil threads were observed throughout the cerebral cortex. Myelinated fiber loss was seen in the hemispheric white matter. Also, amyloid angiopathy and parenchymal Aβ deposition were severe in the cerebellum.
A CT scan of the proband’s brain at age 70 showed mild diffuse cerebral atrophy, and a PET scan at 71 revealed hypometabolism in the posterior parietal region of the left cerebral hemisphere.
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, 57.68 for F176V, was strongly associated with AD age at onset, as well as biomarker and cognitive trajectories across multiple PSEN1 variants.
This variant’s PHRED-scaled CADD score, which integrates diverse in silico information, was 17.88, just below the commonly used deleteriousness threshold of 20 (CADD v.1.6, Oct 2023).
Pathogenicity
Alzheimer's Disease : Not Classified*
*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because only one affected carrier has been reported without a formal AD diagnosis. Moreover, cosegregation data are lacking, and the variant is absent, or very rare, in the gnomAD database.
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.
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.
BP4-P
Multiple lines of computational evidence suggest no impact on 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 less than 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: 16 Oct 2023
References
Paper Citations
- Ghetti B, Oblak A, Richardson R, Epperson F, Murrell J. Familial dementia associated with the novel PSEN1 F176V mutation. Brain Pathol. 2014;24(suppl 1):39-103 Epub 2014 Sep 12.
- 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.
Further Reading
No Available Further Reading
Protein Diagram
Primary Papers
- Ghetti B, Oblak A, Richardson R, Epperson F, Murrell J. Familial dementia associated with the novel PSEN1 F176V mutation. Brain Pathol. 2014;24(suppl 1):39-103 Epub 2014 Sep 12.
Other mutations at this position
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