Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic, Myoclonus : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Myoclonus
Position: (GRCh38/hg38):Chr14:73192843 T>G
Position: (GRCh37/hg19):Chr14:73659551 T>G
dbSNP ID: rs63750634
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTG to GTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This variant was identified in two members of a Japanese family suffering from Alzheimer's disease. They both had progressive memory loss with disorientation starting at approximately 50 years of age and developed myoclonus with frequent tonic-clonic seizures several years later. The mutation was identified in the proband by direct sequencing of PSEN1. It was found in the other affected individual, but not in an unaffected family member, nor in a group of Japanese controls. Moreover, the variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology

Neuropathological data are unavailable, but MRI revealed diffuse cerebral atrophy and SPECT showed severe cortical hypoperfusion.

Biological Effect

Unknown. However, 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 : 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.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP1-M

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. L250V: At least one family with 2 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)

Mutations

PSEN1 L250V

Quick Links

Overview

Findings

Pathogenicity

Alzheimer's Disease : Likely Pathogenic

PM1-M

PM2-M

PM5-M

PP1-M

PP2-P

PP3-P

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References

Paper Citations

External Citations

Further Reading

Protein Diagram

Primary Papers

Other mutations at this position

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