Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73664780 C>G
dbSNP ID: rs63750886
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Deletion; Missense
Codon Change: CTG to GTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8


This mutation was detected in a large pedigree (Tas-1) affected by early onset Alzheimer’s disease. The reported pedigree shows 13 affected individuals over three generations in a pattern consistent with autosomal-dominant inheritance. Presenting clinical features were typical of AD, starting with difficulties in activities of daily living followed by progressive deficits in memory, language, and visuo-spatial skills. Severe dementia typically developed over a span of several years. Myoclonus was a late feature, but spastic paraparesis was not observed. The onset of symptoms ranged from 43 years to the early 60s (mean: 49 years). The age at death ranged from 52 to 65 years, with one affected individual still living at 68 years at the time of the report.

DNA from 18 family members, including five affected individuals, was assessed. All affected individuals were mutation carriers, consistent with L271V conferring pathogenicity in this kindred (Kwok et al., 2003). Linkage analysis of the co-segregation of the mutation and the disease phenotype revealed a positive logarithm of odds ratio (LOD) score (1.8, θ = 0).

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


Two affected members of the Tas-1 pedigree were examined neuropathologically. One died of pulmonary emboli at the age of 60, the other of bronchopneumonia at age 57. Macroscopically, both brains showed considerable atrophy of the temporal and posterior white matter with enlargement of the lateral ventricles. The locus coeruleus was depigmented in both cases. Microscopically, a large number of plaques were noted in the neocortex (CERAD rating: severe). Many of the plaques were a variant type: large, non-cored plaques without neuritic dystrophy, reminiscent of cotton-wool plaques (Kwok et al., 2003).

Biological Effect

This mutation affects splicing such that exon 8 is more frequently excluded from transcripts. It also results in an amino acid replacement (D257A) at the splice junction of exons 7 and 9. The effects of these alterations are unclear, however, with different assays yielding contradictory results. In Cos-7 cells, when co-expressed with mutant APP carrying the Swedish mutation, the L271V mutation increased levels of secreted Aβ42 compared with wild-type PSEN1 (Kwok et al., 2003). A similar increase in secreted Aβ42 was observed in HEK293 cells co-expressing wild-type APP (751) (Dumanchin et al., 2006); however, no effect on Aβ production was found in neuroblastoma cells expressing the PSEN1 mutant (Morihara et al., 2000). Moreover, an in vitro  assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed abrogation of both Aβ40 and Aβ42 production (Sun et al., 2017).

L271 is within a region that undergoes a dramatic conformational change as a result of APP binding (Zhou et al., 2019; Jan 2019 news). The region moves towards the APP β-strand, forming a new α-helix (TM6a) that interacts with residues in PSEN1's second transmembrane domain. 

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted L271V is damaging (Xiao et al., 2021). These authors classified the variant as likely pathogenic using the ACMG-AMP guidelines (Richards et al., 2015).


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.


Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. L271V: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.


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.


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. L271V: At least one family with >=3 affected carriers and >=1 unaffected noncarriers.


Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.


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: 28 Feb 2022


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News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer's disease with non-cored plaques and no neuritic dystrophy. J Biol Chem. 2003 Feb 28;278(9):6748-54. PubMed.
  2. . Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques. Hum Mutat. 2006 Oct;27(10):1063. PubMed.
  3. . Absence of endoproteolysis but no effects on amyloid beta production by alternative splicing forms of presenilin-1, which lack exon 8 and replace D257A. Brain Res Mol Brain Res. 2000 Dec 28;85(1-2):85-90. PubMed.
  4. . 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.
  5. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  6. . 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.
  7. . 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.

Other Citations

  1. Swedish mutation

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer's disease with non-cored plaques and no neuritic dystrophy. J Biol Chem. 2003 Feb 28;278(9):6748-54. PubMed.


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