Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192805 T>G
Position: (GRCh37/hg19):Chr14:73659513 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTT to TGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was identified in a French study that screened 129 individuals with sporadic AD diagnosed according to the National Institute of Aging–Alzheimer’s Association criteria with an age at onset below 51 (Lanoiselée et al., 2017). The mutation carrier had symptoms emerging at age 25, and a disease duration of 14 years. The carrier was homozygous for the APOE 3 allele. It is unknown if the mutation arose de novo, as parental DNA was unavailable. The mutation was absent from the exome database ExAC, including ~60,000 controls.

Neuropathology
Neuropathological data are unavailable, but functional imaging using PET/SPECT of one carrier revealed parieto-temporo-frontal hypoperfusion (Lacour et al., 2019). Based on this carrier's description, they are likely the same carrier as originally described by Lanoiselée and colleagues (Lanoiselée et al., 2017).

Biological Effect
The biological effect of this mutation is unknown. Codon 237 is evolutionarily conserved across human PSEN1, mouse PSEN1, and Caenorhabditis elegans Sel-12 protein, as well as between human PSEN1 and PSEN2 (Sodeyama et al., 2001). Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, the phenylalanine at this position helps form a hydrophobic pocket in the substrate-binding pore (Zhou et al., 2019; Jan 2019 news). As described in another cryo-EM study, substitution of phenylalanine with cysteine, a smaller hydrophylic residue, is expected to reduce the strength of the PSEN1-APP hydrophobic interaction (Guo et al., 2024; Jun 2024 news).

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). Moreover, a pathogenic mutation, F237L, has been identified at the same amino acid position.

Based on the pathogenicity criteria developed by Guerreiro and colleagues (Guerreiro et al., 2010), this mutation was classified as probably pathogenic (Lanoiselée et al., 2017).

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.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. F237C: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

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.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

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)

Last Updated: 13 Jun 2024

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References

News Citations

Mutations Citations

Paper Citations

Lanoiselée HM, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, Richard AC, Pasquier F, Rollin-Sillaire A, Martinaud O, Quillard-Muraine M, de la Sayette V, Boutoleau-Bretonniere C, Etcharry-Bouyx F, Chauviré V, Sarazin M, le Ber I, Epelbaum S, Jonveaux T, Rouaud O, Ceccaldi M, Félician O, Godefroy O, Formaglio M, Croisile B, Auriacombe S, Chamard L, Vincent JL, Sauvée M, Marelli-Tosi C, Gabelle A, Ozsancak C, Pariente J, Paquet C, Hannequin D, Campion D, collaborators of the CNR-MAJ project. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
Lacour M, Quenez O, Rovelet-Lecrux A, Salomon B, Rousseau S, Richard AC, Quillard-Muraine M, Pasquier F, Rollin-Sillaire A, Martinaud O, Zarea A, de la Sayette V, Boutoleau-Bretonniere C, Etcharry-Bouyx F, Chauviré V, Sarazin M, le Ber I, Epelbaum S, Jonveaux T, Rouaud O, Ceccaldi M, Godefroy O, Formaglio M, Croisile B, Auriacombe S, Magnin E, Sauvée M, Marelli C, Gabelle A, Pariente J, Paquet C, Boland A, Deleuze JF, Campion D, Hannequin D, Nicolas G, Wallon D, collaborators of the CNR-MAJ. Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer's Disease Before 51 Years. J Alzheimers Dis. 2019;71(1):227-243. PubMed.
Sodeyama N, Iwata T, Ishikawa K, Mizusawa H, Yamada M, Itoh Y, Otomo E, Matsushita M, Komatsuzaki Y. Very early onset Alzheimer's disease with spastic paraparesis associated with a novel presenilin 1 mutation (Phe237Ile). J Neurol Neurosurg Psychiatry. 2001 Oct;71(4):556-7. PubMed.
Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
Guo X, Li H, Yan C, Lei J, Zhou R, Shi Y. Molecular mechanism of substrate recognition and cleavage by human γ-secretase. Science. 2024 Jun 7;384(6700):1091-1095. Epub 2024 Jun 6 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 F237C

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