Mutations

PSEN1 A164V

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3, BS3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73186863 C>T
Position: (GRCh37/hg19):Chr14:73653571 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCC to GTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was described in a 75-year-old man who met NINCDS-ADRDA criteria for probable AD (Roeber et al., 2015). In addition to memory problems, his symptoms included language and speech impairments, and motor symptoms including dysphagia, spasticity, brisk reflexes, and recurrent falls. The patient had a positive family history for dementia, but specifics were not reported.

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

Neuropathology

Neuropathological data are not available, but cerebral MRI showed generalized atrophy of the brain with pronounced involvement of the anterior temporal lobe, including the hippocampus (Roeber et al., 2015).

Biological Effect

A study that examined a range of Aβ peptides produced by human embryonic kidney cells expressing this mutant and lacking endogenous PSEN1 and PSEN2 found that the Aβ42/Aβ40 and the Aβ37/Aβ42 ratios, both indicators of reduced Aβ trimming activity, were similar to those of controls (Liu et al., 2022; Apr 2022 news). 

However, 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 (Roeber et al., 2015; Xiao et al., 2021).

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.

BS3-S

Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing.

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

Last Updated: 17 Oct 2023

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References

News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?

Paper Citations

  1. Roeber S, Müller-Sarnowski F, Kress J, Edbauer D, Kuhlmann T, Tüttelmann F, Schindler C, Winter P, Arzberger T, Müller U, Danek A, Kretzschmar HA. Three novel presenilin 1 mutations marking the wide spectrum of age at onset and clinical patterns in familial Alzheimer's disease. J Neural Transm (Vienna). 2015 Dec;122(12):1715-9. Epub 2015 Sep 8 PubMed.
  2. Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; 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,

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Roeber S, Müller-Sarnowski F, Kress J, Edbauer D, Kuhlmann T, Tüttelmann F, Schindler C, Winter P, Arzberger T, Müller U, Danek A, Kretzschmar HA. Three novel presenilin 1 mutations marking the wide spectrum of age at onset and clinical patterns in familial Alzheimer's disease. J Neural Transm (Vienna). 2015 Dec;122(12):1715-9. Epub 2015 Sep 8 PubMed.

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