Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Parkinsonism : Not Classified
ACMG/AMP Pathogenicity Criteria: PS2, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73217168 T>G
Position: (GRCh37/hg19):Chr14:73683876 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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.

Pathogenicity

Alzheimer's Disease : Pathogenic*

*This variant was found in a single de novo case, and was complicated by a family history of extrapyramidal disease with several associated recessive mutations.

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

PS2-S

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.

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: 22 Feb 2022

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References

Mutations Citations

Paper Citations

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.
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.

Mutations

PSEN1 V391G

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