Mutations

PSEN1 L232F

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192789 C>T
Position: (GRCh37/hg19):Chr14:73659497 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTC to TTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This variant was identified in a 59-year-old Dutch patient diagnosed with early onset Alzheimer’s disease (Küçükali et al., 2022). The patient was part of the EMIF-AD MBD study, a European multicenter cohort including individuals with AD and mild cognitive impairment (MCI).

This variant was absent from the gnomAD variant database (v2.1.1, Jan 2023).

Neuropathology
Neuropathological data are unavailable, but cerebrospinal fluid biomarkers were consistent with AD (Küçükali et al., 2022).

Biological Effect
The biological effect of this variant is unknown, but its PHRED-scaled CADD score, which integrates diverse information in silico, was 26.1, suggesting a deleterious effect (Küçükali et al., 2022). Also of note, a carrier with a different substitution at this position, L232F, was diagnosed with early onset AD.

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-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)

Last Updated: 23 Jan 2023

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References

Mutations Citations

  1. PSEN1 L232P

Paper Citations

  1. Küçükali F, Neumann A, Van Dongen J, De Pooter T, Joris G, De Rijk P, Ohlei O, Dobricic V, Bos I, Vos SJ, Engelborghs S, De Roeck E, Vandenberghe R, Gabel S, Meersmans K, Tsolaki M, Verhey F, Martinez-Lage P, Tainta M, Frisoni G, Blin O, Richardson JC, Bordet R, Alzheimer's Disease Neuroimaging Initiative (ADNI), Scheltens P, Popp J, Peyratout G, Johannsen P, Frölich L, Freund-Levi Y, Streffer J, Lovestone S, Legido-Quigley C, Kate MT, Barkhof F, Zetterberg H, Bertram L, Strazisar M, Visser PJ, Van Broeckhoven C, Sleegers K, EMIF-AD Study Group. Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits. Alzheimers Dement. 2023 Jun;19(6):2317-2331. Epub 2022 Dec 4 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Küçükali F, Neumann A, Van Dongen J, De Pooter T, Joris G, De Rijk P, Ohlei O, Dobricic V, Bos I, Vos SJ, Engelborghs S, De Roeck E, Vandenberghe R, Gabel S, Meersmans K, Tsolaki M, Verhey F, Martinez-Lage P, Tainta M, Frisoni G, Blin O, Richardson JC, Bordet R, Alzheimer's Disease Neuroimaging Initiative (ADNI), Scheltens P, Popp J, Peyratout G, Johannsen P, Frölich L, Freund-Levi Y, Streffer J, Lovestone S, Legido-Quigley C, Kate MT, Barkhof F, Zetterberg H, Bertram L, Strazisar M, Visser PJ, Van Broeckhoven C, Sleegers K, EMIF-AD Study Group. Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits. Alzheimers Dement. 2023 Jun;19(6):2317-2331. Epub 2022 Dec 4 PubMed.

Other mutations at this position

View Table

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