Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73653599 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTG to TTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was detected in an individual of Spanish descent described as having sporadic early-onset Alzheimer's disease (Jin et al., 2012). Symptom onset occurred at age 50, but further clinical details were not reported. APOE genotype was ε3/ε3.

The mutation was also found in a woman from a large cohort study in South China in which 14 genes associated with neurodegenerative dementias were sequenced in 1795 patients (Jiao et al., 2021). The proband was diagnosed with AD and her symptoms, which included memory impairment and mental and behavioral changes, began at age 37. She had an APOE3/4 genotype.

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

Neuropathology

Unknown. Compared with carriers of other familial AD mutations, an L173F carrier (nucleotide change unspecified) had a similar ratio of Aβ38/Aβ40 in their cerebrospinal fluid, with both peptides present at very low levels (Kakuda et al., 2021). Also, both Aβ42 and Aβ43 levels were very low.

Biological Effect

The biological effect of this mutation is uncertain. The synonymous L173F (G>C) mutation caused an increase in Aβ42 secretion and an elevated Aβ42/Aβ40 ratio (Kasuga et al., 2009). A subsequent cell-based study also found L173F (nucleotide change unspecified) increased the Aβ42/Aβ40 ratio, but reduced production of both Aβ42 and Aβ40 (Liu et al., 2022; Apr 2022 news). Moreover, in this same study, the Aβ37/Aβ42 ratio, a measurement that outperformed the Aβ42/Aβ40 ratio as a biomarker for distinguishing between control and AD samples, was similar to that of controls.

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 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).

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS1-S

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

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. L173F (G>T): 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: 09 Nov 2022

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References

Mutations Citations

News Citations

Paper Citations

Jin SC, Pastor P, Cooper B, Cervantes S, Benitez BA, Razquin C, Goate A, Ibero-American Alzheimer Disease Genetics Group Researchers, Cruchaga C. Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer's disease Ibero-American cohort. Alzheimers Res Ther. 2012 Aug 20;4(4):34. PubMed.
Jiao B, Liu H, Guo L, Xiao X, Liao X, Zhou Y, Weng L, Zhou L, Wang X, Jiang Y, Yang Q, Zhu Y, Zhou L, Zhang W, Wang J, Yan X, Li J, Tang B, Shen L. The role of genetics in neurodegenerative dementia: a large cohort study in South China. NPJ Genom Med. 2021 Aug 13;6(1):69. PubMed.
Kakuda N, Takami M, Okochi M, Kasuga K, Ihara Y, Ikeuchi T. Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. PubMed.
Kasuga K, Ohno T, Ishihara T, Miyashita A, Kuwano R, Onodera O, Nishizawa M, Ikeuchi T. Depression and psychiatric symptoms preceding onset of dementia in a family with early-onset Alzheimer disease with a novel PSEN1 mutation. J Neurol. 2009 Aug;256(8):1351-3. PubMed.
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.
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.
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.

Mutations

PSEN1 L173F (G>T)

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