Mutations

PSEN1 L174R

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: Chr14:73653601 T>G
dbSNP ID: rs63751025
Coding/Non-Coding: Coding
Mutation Type: Point, 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. 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

The biological effect of this mutation is unknown. However, the mutation is a nonconservative substitution in an evolutionarily conserved position, and other AD-related mutations 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 : 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: it was found in a single affected family without clear evidence of cosegregation or a functional effect, and it 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. 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: 22 Feb 2022

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References

News Citations

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

Paper Citations

  1. . Novel PS1 mutation in a Bavarian kindred with familial Alzheimer disease. Alzheimer Dis Assoc Disord. 2004 Oct-Dec;18(4):256-8. PubMed.
  2. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  3. . 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

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Novel PS1 mutation in a Bavarian kindred with familial Alzheimer disease. Alzheimer Dis Assoc Disord. 2004 Oct-Dec;18(4):256-8. PubMed.

Other mutations at this position

Alzpedia

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