Mutations

PSEN1 L262V

Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Reference Assembly: GRCh37/hg19
Position: Chr14:73664753 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTG to GTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

The L262V mutation was found in a large French study reporting 56 new families with autosomal-dominant, early onset Alzheimer's disease. All probands met NINCDS-ADRDA criteria for probable AD and had a family history of disease (Wallon et al., 2012).

The mutation was detected in one family with three confirmed carriers and eight affected family members. Age of onset ranged from 54 to 63 years old, with a disease duration of approximately eight years. Although the mutation was described as co-segregating with disease in this family, healthy non-carriers were not reported.

Another study reported the L262V mutation in two Turkish siblings with a family history of dementia (Lohmann et al., 2012). Both siblings developed symptoms around age 50; however, the presenting symptoms were different, leading to diagnoses of AD and frontotemporal dementia, respectively. One sibling presented with depression, inappropriate behavior, and memory problems. Frontal symptoms then developed, including disinhibited speech and perseveration, along with temporospatial disorientation. Prominent symptoms in the other sibling included disorientation, aphasia, and memory deficits.

The mother of these two patients, as well as their maternal aunt, reportedly suffered from dementia. Both died at approximately 70 years of age after a rapid decline. A cousin was also affected by memory problems, bringing the number of affected individuals up to five in two generations, as shown in the reported pedigree, which indicates at least two consanguineous marriages.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology

Unknown.

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, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

The L262V mutation was classified by Wallon et al., 2012 as definitely pathogenic according to the algorithm proposed by Guerreiro et al., 2010 and as likely pathogenic by Xiao et al., 2021 using the ACMG-AMP guidelines (Richards et al., 2015).

 

Last Updated: 23 Sep 2021

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References

Paper Citations

  1. . The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. PubMed.
  2. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
  3. . 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.
  4. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
  5. . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. PubMed.
  2. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.

Other mutations at this position

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