Mutations

PSEN1 T291A

Overview

Pathogenicity: Alzheimer's Disease : Benign, Parkinsonism : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PP2, PP3, BP5, BS2
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73206388 A>G
Position: (GRCh37/hg19):Chr14:73673096 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACA to GCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 9

Findings

This variant was initially identified in a Scottish-Italian man who also carried a variant classified as pathogenic, PSEN1 A434T (Ryan et al., 2016).  He developed memory impairment and a gait disorder at age 42. Both his mental and motor symptoms worsened rapidly, resulting in severe cognitive impairment, development of various pyramidal and extrapyramidal signs, and death at age 47.  Family history was limited, but his father had cognitive impairment and a shuffling gait before death due to brain hemorrhage at age 34.

Two non-demented Hispanic carriers, participating in the Alzheimer’s Disease Sequencing Project as controls, were subsequently identified (Lee et al., 2023, see suppl table 9).

The variant is present in the general gnomAD variant database with an allele count of 1 and a frequency of 0.000003978 (gnomAD v2.1.1, July 2021). 

Neuropathology
Autopsy revealed AD pathology with cotton wool plaques, diffuse amyloid deposits, and severe amyloid angiopathy. Moreover, brain MRI showed extensive white matter hyperintensities and generalized atrophy before death.

Biological Effect
The biological effect of this mutation is unknown. However, the mutation site is conserved across species and, although some in silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Ryan et al., 2016, Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score, above 20 (CADD v.1.6, Sep 2021).

Pathogenicity

Alzheimer's Disease : Benign

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

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.

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.

BP5-S

Variant found in a case with an alternate molecular basis for disease. T291A: The single carrier also carried PSEN1 A434T which has been classified as pathogenic.

BS2-S

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.

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 Nov 2023

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References

Mutations Citations

  1. PSEN1 A434T

Paper Citations

  1. Ryan NS, Nicholas JM, Weston PS, Liang Y, Lashley T, Guerreiro R, Adamson G, Kenny J, Beck J, Chavez-Gutierrez L, de Strooper B, Revesz T, Holton J, Mead S, Rossor MN, Fox NC. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. Epub 2016 Oct 21 PubMed.
  2. Lee W-P, Choi SH, Shea MG, Cheng P-L, Dombroski BA, Pitsillides AN, Heard-Costa NL, Wang H, Bulekova K, Kuzma AB, Leung YY, Farrell JJ, Lin H, Naj A, Blue EE, Nusetor F, Wang D, Boerwinkle E, Bush WS, Zhang X, DeJager PL, Dupuis J, Farrer LA, Fornage M, Martin E, Pericak-Vance M, Seshadri S, Wijsman EM, Wang L-S, Schellenberg GD, Destefano AL, Haines JL, Peloso GM. Association of Common and Rare Variants with Alzheimer's Disease in over 13,000 Diverse Individuals with Whole-Genome Sequencing from the Alzheimer's Disease Sequencing Project. 2023 Sep 02 10.1101/2023.09.01.23294953 (version 1) medRxiv.
  3. 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
  2. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Ryan NS, Nicholas JM, Weston PS, Liang Y, Lashley T, Guerreiro R, Adamson G, Kenny J, Beck J, Chavez-Gutierrez L, de Strooper B, Revesz T, Holton J, Mead S, Rossor MN, Fox NC. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. Epub 2016 Oct 21 PubMed.

Other mutations at this position

View Table

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