Mutations
PSEN1 H214N
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Overview
Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity
Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical
Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659443 C>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA
Change: Substitution
Expected RNA
Consequence: Substitution
Expected Protein
Consequence: Missense
Codon
Change: CAC to AAC
Reference
Isoform: PSEN1 Isoform 1 (467 aa)
Genomic
Region: Exon 7
Findings
This PSEN1 mutation was found in a Caucasian woman from Italy who met clinical criteria for probable Alzheimer’s disease (Piccoli et al., 2016). Her symptoms started at age 46 with executive dysfunction. She had a family history of dementia: Her maternal grandfather developed dementia at 50 years of age and died at 55. The proband’s mother presented with memory decline at age 55, and died at 62. Segregation with disease could not be determined.
This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).
Neuropathology
Unknown. CT scan showed diffuse cerebral atrophy more pronounced in medial temporal lobes.
Biological Effect
A study that examined a range of Aβ peptides generated by this variant in human embryonic kidney cells lacking endogenous PSEN1 and PSEN2 and expressing this mutant revealed increased Aβ42/Aβ40 and decreased Aβ37/Aβ42, both indicators of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Of note, in this study, Aβ37/Aβ42 outperformed Aβ42/Aβ40 as a biomarker for distinguishing between control and AD samples.
A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue 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, several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) predicted it is damaging (Piccoli et al., 2016, Xiao et al., 2021).
Pathogenicity
Alzheimer's Disease : Not Classified*
*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, 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. H214N: Variant is at edge of a mutational hot spot; 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.
PM5-M
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
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: 15 Nov 2022
References
News Citations
- Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?
- CryoEM γ-Secretase Structures Nail APP, Notch Binding
Paper Citations
- Piccoli E, Rossi G, Rossi T, Pelliccioni G, D'Amato I, Tagliavini F, Di Fede G. Novel PSEN1 mutations (H214N and R220P) associated with familial Alzheimer's disease identified by targeted exome sequencing. Neurobiol Aging. 2016 Apr;40:192.e7-11. Epub 2016 Feb 28 PubMed.
- Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; 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.
- 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.
External Citations
Further Reading
No Available Further Reading
Protein Diagram
Primary Papers
- Piccoli E, Rossi G, Rossi T, Pelliccioni G, D'Amato I, Tagliavini F, Di Fede G. Novel PSEN1 mutations (H214N and R220P) associated with familial Alzheimer's disease identified by targeted exome sequencing. Neurobiol Aging. 2016 Apr;40:192.e7-11. Epub 2016 Feb 28 PubMed.
Other mutations at this position
Alzpedia
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