Mutations

PSEN1 L166H

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73653577 T>A
dbSNP ID: rs63750265
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTT to CAT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was identified in an Italian woman who began to experience progressive memory loss at age 30. She did not have a strong family history of dementia. Notably, her parents did not show signs of dementia before their deaths at age 63 and 83 years, and her grandparents and five older siblings were likewise unaffected. A brother and a sister of her paternal grandparents were both affected by late-onset dementia, but no further details were available. In addition to cognitive impairment, the patient developed extrapyramidal signs, myoclonus, postural tremor, and persistent blinking. Segregation with disease could not be determined as only the patient's DNA was analyzed; however, it was noted that the mutation was absent in 95 unrelated healthy Italian subjects (Pantieri et al., 2005).

This variant was also reported in a subsequent study from Italy, including some of the same authors (Bartoletti-Stella et al., 2022). It is unclear if the reported carriers in the two studies refer to the same subject.

Neuropathology

Unknown. MRI showed marked hippocampal atrophy and cortical atrophy, especially in the insula and the peri-insular temporal lobe. SPECT imaging showed bilateral hypometabolism in the parietal and frontal lobes.

Biological Effect

Unknown. 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).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (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.

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. L166H: 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.

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: 06 Jan 2023

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References

News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. Pantieri R, Pardini M, Cecconi M, Dagna-Bricarelli F, Vitali A, Piccini A, Russo R, Borghi R, Tabaton M. A novel presenilin 1 L166H mutation in a pseudo-sporadic case of early-onset Alzheimer's disease. Neurol Sci. 2005 Dec;26(5):349-50. PubMed.
  2. Bartoletti-Stella A, Tarozzi M, Mengozzi G, Asirelli F, Brancaleoni L, Mometto N, Stanzani-Maserati M, Baiardi S, Linarello S, Spallazzi M, Pantieri R, Ferriani E, Caffarra P, Liguori R, Parchi P, Capellari S. Dementia-related genetic variants in an Italian population of early-onset Alzheimer's disease. Front Aging Neurosci. 2022;14:969817. Epub 2022 Sep 5 PubMed.
  3. 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.
  4. 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Pantieri R, Pardini M, Cecconi M, Dagna-Bricarelli F, Vitali A, Piccini A, Russo R, Borghi R, Tabaton M. A novel presenilin 1 L166H mutation in a pseudo-sporadic case of early-onset Alzheimer's disease. Neurol Sci. 2005 Dec;26(5):349-50. PubMed.

Other mutations at this position

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Alzpedia

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