Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Parkinsonism : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73683876 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTT to GGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation was identified in a patient diagnosed with rapidly progressing, early AD with extrapyramidal symptoms (Lou et al., 2017). In addition to the V391G mutation, the patient carried recessive gene variants associated with extrapyramidal disease (PANK2, SYNE1, ZNF592) and had several family members who had been diagnosed with extrapyramidal disorders, including Parkinson’s disease and head tremor. The proband’s first symptoms, difficulty walking and action tremor, appeared at age 23. Within six months, motor symptoms had progressed, including the development of dysarthria and spasmodic torticollis, and impairments in short-term memory, spatial and temporal orientation, and verbal fluency developed. The unaffected parents of the patient did not carry the mutation (paternity was confirmed), indicating the mutation arose de novo.

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

Neuropathology
Although neuropathology data are unavailable, MRI showed generalized mild cortical and subcortical atrophy, hippocampal shrinkage, and enlarged ventricles.

Biological Effect
The biological effect of this mutation is unknown, but 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 (Lou et al., 2017, Xiao et al., 2021). In addition, V391F, another mutation at the same site, was classified as pathogenic.

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References

Mutations Citations

1. PSEN1 V391F

Paper Citations

1. Lou F, Luo X, Li M, Ren Y, He Z. Very early-onset sporadic Alzheimer's disease with a de novo mutation in the PSEN1 gene. Neurobiol Aging. 2017 May;53:193.e1-193.e5. Epub 2017 Jan 6 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

Further Reading

No Available Further Reading