Overview

Pathogenicity: Alzheimer's Disease : Not Classified, Parkinsonism : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73673096 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ACA to GCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 9

Findings

This mutation was identified in a Scottish-Italian man who also carried the PSEN1 A434T mutation (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.

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).

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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. 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