Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192861 T>A
Position: (GRCh37/hg19):Chr14:73659569 T>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TAT to AAT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was found in a Chinese family including five members spanning two generations affected by early onset dementia (Li et al., 2019). The proband presented with short-term memory impairment at 40 years of age. At 41, she was diagnosed with early onset AD and showed progressive mental decline, including disorientation, confusion, and impaired cognitive function. In addition, at age 42, she developed static tremor, kinetic tremor, hypermyotonia, impaired speech, and generalized tonic-clonic seizures. Three of the proband’s siblings and her mother suffered from severe memory impairment in their late 30s or early 40s.

Two mutations were found in the proband’s PSEN1 gene: Y256N and V255V, a synonymous mutation. The former was also identified in two of the proband’s affected siblings, but not in her unaffected father, nor in an unaffected sibling. The mutation was also absent from 200 Chinese healthy controls and two genetic variant databases (ExAC and 1000 Genomes).

Neuropathology
Although neuropathological data are unavailable, a brain MRI of the proband revealed bilateral temporal lobe and hippocampal atrophy.

Biological Effect
The biological effect of this variant is unknown, but several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, MutPred2, SNAP, and Reve) predicted this variant is damaging (Li et al., 2019, Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Likely Pathogenic

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

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.

PP1-S

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. Y256N: At least one family with >=3 affected carriers and >=1 unaffected noncarriers.

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

Paper Citations

Li YS, Yang ZH, Zhang Y, Yang J, Shang DD, Zhang SY, Wu J, Ji Y, Zhao L, Shi CH, Xu YM. Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer's Disease. Aging Dis. 2019 Aug;10(4):908-914. 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 Y256N

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