Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659506 C>G
dbSNP ID: rs63751130
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTG to GTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7


This mutation has been reported in two families from the United Kingdom and Mexico. The UK kindred, Family 267, included six affected individuals over three generations. The mean age at onset was reported as 47, with a range of 44-50 years. The diagnosis of Alzheimer's disease was confirmed postmortem in at least one case. The mutation appeared to segregate with disease; it was present in two affected family members, and absent in 100 unrelated control individuals (Janssen et al., 2003).

The L235V mutation was also reported in a Mexican family with familial dementia starting around age 48. Further clinical details were not described, although 11 asymptomatic female family members participated in a depression screen. Mutation carriers had a higher incidence of depression than non-carriers, even when they were naïve to their mutation status, supporting the hypothesis that depression is an early clinical feature related to AD pathology (Ringman et al., 2004).

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


Neuropathology consistent with a diagnosis of AD was found in at least one case (Janssen et al., 2003).

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it generates less Aβ40 and Aβ42 than the wildtype protein, without changing the Aβ42/Aβ40 ratio (Sun et al., 2017). In addition, the association of L235V with depression led researchers to study its effect on monoamine-oxidase-A (MAO-A), an enzyme that degrades serotonin and noradrenaline. Expression of mutant PSEN1 in a murine hippocampal cell line resulted in higher MAO-A activity compared with cells expressing wild-type PSEN1, suggesting that L235V may predispose to depression by affecting neurotransmitter metabolism. In addition, co-immunoprecipitation experiments suggested a possible direct interaction of PSEN1 with MAO-A (Pennington et al., 2011).

Last Updated: 16 Jul 2021


No Available Comments

Make a Comment

To make a comment you must login or register.


Paper Citations

  1. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
  2. . Female preclinical presenilin-1 mutation carriers unaware of their genetic status have higher levels of depression than their non-mutation carrying kin. J Neurol Neurosurg Psychiatry. 2004 Mar;75(3):500-2. PubMed.
  3. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
  4. . Alzheimer disease-related presenilin-1 variants exert distinct effects on monoamine oxidase-A activity in vitro. J Neural Transm. 2011 Jul;118(7):987-95. PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.

Other mutations at this position


Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.