Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192790 T>C
Position: (GRCh37/hg19):Chr14:73659498 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTC to CCC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was identified in a Korean patient with early onset Alzheimer’s disease and a family history of dementia (Park et al., 2017). Memory decline was first noticed when the proband was 37 years old, and within a year he was unable to live independently. He received a clinical diagnosis of dementia at age 41, and experienced his first tonic-clonic seizure at age 42. The proband has six siblings, three of whom also suffered from dementia, with symptom onset in their 40s or 50s; one brother was healthy at age 59, another brother died in his 20s, and the health status of the remaining brother is unknown. The mother of the proband was diagnosed with dementia in her 40s and the father died of cancer at age 54 with no reported symptoms of dementia. The family history is thus consistent with an autosomal-dominant pattern of inheritance, but DNA from family members was not available for segregation analysis.

The mutation was not found in the Korean Reference Genome Database, which contains whole-genome sequencing data on 622 healthy Korean individuals, nor was it seen in the ExAC or 1000 Genomes databases.

Neuropathology

Unknown. However, MRI of the proband revealed diffuse cortical atrophy, especially in the frontal and parietal lobes.

Biological Effect

Unknown. 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 (Xiao et al., 2021). Amino acid 233 is in the fifth transmembrane domain, and three-dimensional modeling using Raptor X showed that the leucine-to-proline substitution might introduce a kink in this region (Park et al., 2017).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

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.

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

Park J, An SS, Giau VV, Shim K, Youn YC, Bagyinszky E, Kim S. Identification of a novel PSEN1 mutation (Leu232Pro) in a Korean patient with early-onset Alzheimer's disease and a family history of dementia. Neurobiol Aging. 2017 Aug;56:212.e11-212.e17. Epub 2017 Apr 26 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 L232P

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