Mutations

PSEN1 L226R

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659480 T>G
dbSNP ID: rs63749961
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTC to CGC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This variant was first reported in a case of familial early onset Alzheimer's disease in the U.S. (Coleman et al., 2004). It was subsequently found in a man from a large cohort study in South China in which 14 genes associated with neurodegenerative dementias were sequenced in 1795 patients (Jiao et al., 2021). This carrier had AD with an age at onset of 44 years and a family history of the disease. He suffered from memory impairment, as well as from mental and behavioral changes. He had an APOE 3/4 genotype.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology

In one individual, neuropathology was found to be consistent with AD, including numerous neuritic plaques and neurofibrillary tangles in the hippocampus and neocortex (Coleman et al., 2004).

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, 30.20 for L226R, was strongly associated with AD age at onset, as well as biomarker and cognitive trajectories across multiple PSEN1 variants.

Moreover, this variant's location is consistent with the helical alignment of pathogenic mutations in transmembrane domain 5 (Coleman et al., 2004), and several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted it 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-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.

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: 17 Oct 2023

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References

Paper Citations

  1. Coleman P, Kurlan R, Crook R, Werner J, Hardy J. A new presenilin Alzheimer's disease case confirms the helical alignment of pathogenic mutations in transmembrane domain 5. Neurosci Lett. 2004 Jul 8;364(3):139-40. PubMed.
  2. Jiao B, Liu H, Guo L, Xiao X, Liao X, Zhou Y, Weng L, Zhou L, Wang X, Jiang Y, Yang Q, Zhu Y, Zhou L, Zhang W, Wang J, Yan X, Li J, Tang B, Shen L. The role of genetics in neurodegenerative dementia: a large cohort study in South China. NPJ Genom Med. 2021 Aug 13;6(1):69. PubMed.
  3. 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.
  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.

External Citations

  1. gnomAD v2.1.1

Further Reading

Papers

  1. Ma L, Zhang J, Shi Y, Wang W, Ren Z, Xia M, Zhang Y, Yang M. Gene mutations in a Han Chinese Alzheimer's disease cohort. Brain Behav. 2019 Jan;9(1):e01180. Epub 2018 Dec 14 PubMed.

Protein Diagram

Primary Papers

  1. Coleman P, Kurlan R, Crook R, Werner J, Hardy J. A new presenilin Alzheimer's disease case confirms the helical alignment of pathogenic mutations in transmembrane domain 5. Neurosci Lett. 2004 Jul 8;364(3):139-40. PubMed.

Other mutations at this position

View Table

Alzpedia

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