Mutations

PSEN1 L250V

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic, Myoclonus : Not Classified
Clinical Phenotype: Alzheimer's Disease, Myoclonus
Reference Assembly: GRCh37/hg19
Position: Chr14:73659551 T>G
dbSNP ID: rs63750634
Coding/Non-Coding: Coding
Mutation Type: Point, 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).

Last Updated: 13 Sep 2021

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References

Paper Citations

  1. 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.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Furuya H, Yasuda M, Terasawa KJ, Tanaka K, Murai H, Kira J, Ohyagi Y. A novel mutation (L250V) in the presenilin 1 gene in a Japanese familial Alzheimer's disease with myoclonus and generalized convulsion. J Neurol Sci. 2003 May 15;209(1-2):75-7. PubMed.

Other mutations at this position

View Table

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