Mutations

PSEN1 I437V

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PP2, PP3, BS1
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73685902 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATC to GTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was identified by whole exome sequencing in a Frenchwoman diagnosed with Alzheimer’s disease according to NINDCS-ADRDA criteria (Nicolas et al., 2015). She was 57 years old when symptoms first appeared. Her clinical presentation was consistent with typical AD. Her APOE genotype was E3/E4. She had no family history of AD.

This variant was found in the gnomAD variant database at a frequency of 0.0001592 with an allele count of five (gnomAd v2.1.1, Aug 2021). Of note, the reference population for this variant was relatively small (total allele count 31,408). In the non-neuro dataset, which excludes data from neurological studies, the frequency was 0.0002351 with an allele count of 5 (total allele count 21,268; gnomAD v2.1.1 (non-neuro), Aug 2021). 

Neuropathology

Unknown.

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed reduced production of Aβ40 and Aβ42 compared with wildtype PSEN1, and an Aβ42/Aβ40 ratio that was elevated more than fivefold (Sun et al., 2017). Although some in silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).

Pathogenicity

Alzheimer's Disease : Not Classified

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. I437V: 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.

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.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  I437V: Most carriers were of European ancestry.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 22 Feb 2022

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References

Paper Citations

  1. Nicolas G, Wallon D, Charbonnier C, Quenez O, Rousseau S, Richard AC, Rovelet-Lecrux A, Coutant S, Le Guennec K, Bacq D, Garnier JG, Olaso R, Boland A, Meyer V, Deleuze JF, Munter HM, Bourque G, Auld D, Montpetit A, Lathrop M, Guyant-Maréchal L, Martinaud O, Pariente J, Rollin-Sillaire A, Pasquier F, Le Ber I, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Thomas-Antérion C, Paquet C, Sauvée M, Moreaud O, Gabelle A, Sellal F, Ceccaldi M, Chamard L, Blanc F, Frebourg T, Campion D, Hannequin D. Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.
  2. 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.
  3. 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.

External Citations

  1. gnomAd v2.1.1
  2. gnomAD v2.1.1 (non-neuro)
  3. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Nicolas G, Wallon D, Charbonnier C, Quenez O, Rousseau S, Richard AC, Rovelet-Lecrux A, Coutant S, Le Guennec K, Bacq D, Garnier JG, Olaso R, Boland A, Meyer V, Deleuze JF, Munter HM, Bourque G, Auld D, Montpetit A, Lathrop M, Guyant-Maréchal L, Martinaud O, Pariente J, Rollin-Sillaire A, Pasquier F, Le Ber I, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Thomas-Antérion C, Paquet C, Sauvée M, Moreaud O, Gabelle A, Sellal F, Ceccaldi M, Chamard L, Blanc F, Frebourg T, Campion D, Hannequin D. Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.

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