Mutations

PSEN1 P267L

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198061 C>T
Position: (GRCh37/hg19):Chr14:73664769 C>T
dbSNP ID: rs63750779
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCA to CTA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in a Polish individual who met clinical criteria (NINCDS-ADRDA) for AD (Kowalska et al., 2003). This individual had a family history of dementia and belonged to a pedigree referred to as “H.A.” The reported pedigree shows seven affected individuals over three generations (Kowalska et al., 2004). Segregation with disease could not be established due to lack of DNA from family members. The mutation carrier experienced symptom onset at age 59. APOE genotype was 3/3; further clinical details were not reported.

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

Neuropathology

Unknown.

Biological Effect

The biological effect of this mutation is unknown, but a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue appears to help stabilize the structural re-arrangement of PSEN1 upon APP binding (Zhou et al., 2019; Jan 2019 news). Moreover, 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). These authors classified the variant as likely pathogenic using the ACMG-AMP guidelines (Richards et al., 2015).

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. P267L: 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: 29 Nov 2022

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References

News Citations

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

Paper Citations

  1. Kowalska A, Wender M, Florczak J, Pruchnik-Wolinska D, Modestowicz R, Szczech J, Rossa G, Kozubski W. Molecular genetics of Alzheimer's disease: presenilin 1 gene analysis in a cohort of patients from the Poznań region. J Appl Genet. 2003;44(2):231-4. PubMed.
  2. Kowalska A, Pruchnik-Wolińska D, Florczak J, Modestowicz R, Szczech J, Kozubski W, Rossa G, Wender M. Genetic study of familial cases of Alzheimer's disease. Acta Biochim Pol. 2004;51(1):245-52. PubMed.
  3. 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.
  4. 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.
  5. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. 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.

External Citations

  1. gnomAD v2.1.1

Further Reading

Papers

  1. Kowalska A, Pruchnik-Wolińska D, Florczak J, Szczech J, Kozubski W, Rossa G, Wender M. Presenilin 1 mutations in Polish families with early-onset Alzheimer's disease. Folia Neuropathol. 2004;42(1):9-14. PubMed.

Protein Diagram

Primary Papers

  1. Kowalska A, Wender M, Florczak J, Pruchnik-Wolinska D, Modestowicz R, Szczech J, Rossa G, Kozubski W. Molecular genetics of Alzheimer's disease: presenilin 1 gene analysis in a cohort of patients from the Poznań region. J Appl Genet. 2003;44(2):231-4. PubMed.

Other mutations at this position

View Table

Alzpedia

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