Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73186893 T>G
Position: (GRCh37/hg19):Chr14:73653601 T>G
dbSNP ID: rs63751025
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTG to CGG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was found in two Bavarian sisters from a family including seven individuals affected by dementia, spanning four generations (Klünemann et al., 2004). The sisters developed early memory impairment and severe personality changes, and were initially diagnosed with frontotemporal dementia. Mean age of dementia onset in the family was 48 years, ranging between 46 and 56 years. The mutation was absent from 200 healthy controls and from the gnomAD variant database (gnomAD v2.1.1, June 2021)..

Neuropathology

Neuropathology in one case was consistent with AD, including generalized brain atrophy with the hippocampus and temporal cortex most severely affected (Klünemann et al., 2004). The distribution of amyloid plaques, neurofibrillary tangles, neuropil threads, and dystrophic neurites was consistent with AD Braak stage VI. In addition, abundant Lewy bodies were found in the amygdala and entorhinal cortex.

Biological Effect

A study that examined a range of Aβ peptides produced by human embryonic kidney cells expressing this mutant and lacking endogenous PSEN1 and PSEN2 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. This variant also increased Aβ43 levels nearly fivefold compared with wildtype PSEN1.

This variant is a nonconservative substitution in an evolutionarily conserved position, and other AD-related variants have been reported at this site. Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment suggests mutations in L174 could alter the protein's local conformation and affect the positioning of residues that directly contribute to substrate binding (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 : 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-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. L174R: 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: 01 Dec 2022

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References

News Citations

Paper Citations

Klünemann HH, Rogaeva E, Neumann M, Kretzschmar HA, Kandel M, Toulina A, Sato C, Salehi-Rad S, Pfister K, Klein HE, St George-Hyslop PH. Novel PS1 mutation in a Bavarian kindred with familial Alzheimer disease. Alzheimer Dis Assoc Disord. 2004 Oct-Dec;18(4):256-8. 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.

Mutations

PSEN1 L174R

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