Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192845 G>T
Position: (GRCh37/hg19):Chr14:73659553 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTG to TTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was found in a large North American Aboriginal kindred with early onset familial AD (Butler et al., 2010). In contrast to previously reported families with PSEN1 L250 mutations, the 16 affected members of this kindred did not present with either myoclonus or seizures. The mutation segregated with disease as revealed by its presence in six affected individuals and its absence from two unaffected individuals who were past the median age of onset. It was also absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology

Nueropathology data were unavailable, but CT scans from six affected individuals showed frontal, parietal, and temporal atrophy.

Biological Effect

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 (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : 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. L250F: 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

Butler R, Beattie BL, Thong UP, Dwosh E, Guimond C, Feldman HH, Hsiung GY, Rogaeva E, St George-Hyslop P, Sadovnick AD. A novel PS1 gene mutation in a large Aboriginal kindred. Can J Neurol Sci. 2010 May;37(3):359-64. 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 L250F

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