Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640384 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTG to CCG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This 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 L150P mutation was detected in one individual in a family with six affected individuals. Only the genotype of the proband is known, therefore segregation with disease could not be determined. Age of onset in this family ranged from 54 to 65 years, with a duration of five to 10 years.

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

Neuropathology

Unknown.

Biological Effect

In an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate, Aβ42 production was drastically reduced and Aβ40 production was undetectable (Sun et al., 2017). 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 mutation was classified By Wallon and colleagues as probably pathogenic according to the algorithm proposed by Guerreiro et al., 2010.

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. L150P: Aβ42/Aβ40 ratio increased, but production of both peptides decreased.

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.

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)

Research Models

Induced pluripotent stem cells were generated from skin fibroblasts isolated from a 58-year-old man carrying the mutation (Tubsuwan et al., 2016). An isogenic control line, with the mutation corrected using CRISPR/Cas9, is also available (Poon et al., 2016).

Last Updated: 22 Feb 2022

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References

Paper Citations

Tubsuwan A, Pires C, Rasmussen MA, Schmid B, Nielsen JE, Hjermind LE, Hall V, Nielsen TT, Waldemar G, Hyttel P, Clausen C, Kitiyanant N, Freude KK, Holst B. Generation of induced pluripotent stem cells (iPSCs) from an Alzheimer's disease patient carrying a L150P mutation in PSEN-1. Stem Cell Res. 2016 Jan;16(1):110-2. Epub 2015 Dec 28 PubMed.
Poon A, Schmid B, Pires C, Nielsen TT, Hjermind LE, Nielsen JE, Holst B, Hyttel P, Freude KK. Generation of a gene-corrected isogenic control hiPSC line derived from a familial Alzheimer's disease patient carrying a L150P mutation in presenilin 1. Stem Cell Res. 2016 Nov;17(3):466-469. Epub 2016 Sep 24 PubMed.
Wallon D, Rousseau S, Rovelet-Lecrux A, Quillard-Muraine M, Guyant-Maréchal L, Martinaud O, Pariente J, Puel M, Rollin-Sillaire A, Pasquier F, Le Ber I, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Thomas-Antérion C, Paquet C, Moreaud O, Gabelle A, Sellal F, Sauvée M, Laquerrière A, Duyckaerts C, Delisle MB, Streichenberger N, Lannes B, Frebourg T, Hannequin D, Campion D. 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.
Sun L, Zhou R, Yang G, Shi Y. 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.
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.
Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. 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.

Mutations

PSEN1 L150P

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