Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73171041 G>T
Position: (GRCh37/hg19):Chr14:73637749 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGG to GTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was found in a Chinese man with AD who was first diagnosed with mild cognitive impairment (MCI) at age 55 (Qiu et al., 2019). His memory declined and he developed executive dysfunction during the two years following his initial assessment. His mother first reported memory loss at age 62, and also developed executive dysfunction, as well as visuospatial impairment, with dementia setting in at age 70. The proband’s 64-year-old brother was cognitively healthy. Genetic information was obtained only from the proband, who was homozygous for the APOE 3 allele. The mutation was absent from 100 cognitively normal controls and 100 patients with late-onset AD. It was also absent from several variant databases, including ExAC, Exome Variant Server, 1000 Genomes, ClinVar, and gnomAD.

In a subsequent report from the same research group, a family with five affected members, spanning two generations, with a mean age at onset of 64 was described (Jia et al., 2020). The proband was diagnosed with MCI, with age at onset of 53 years, and an APOE genotype of E3/E3. Three other family members were diagnosed with AD and found to carry the mutation. One cognitively healthy non-carrier was reported, but their age was 59, below the family's mean age at onset. It is unclear if this subsequent report refers to the same family described above.

Neuropathology
Although neuropathological data are unavailable, an MRI of the proband showed bilateral hippocampal atrophy (Qiu et al., 2019).

Biological Effect
Levels of Aβ40 were reduced in the conditioned media of human embryonic kidney cells expressing APPswe and the mutant PSEN1 protein compared with cells expressing APPswe and wildtype PSEN1. Aβ42 levels were similar in the two cell lines, resulting in an elevated Aβ42/Aβ40 ratio (Qiu et al., 2019).

Although multiple in silico algorithms (PANTHER, Mutation Taster, Mutpred, PROVEAN, and PolyPhen-2), predicted the mutation is probably damaging (Qiu et. al., 2019, Jia et al., 2020), another study, using other algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) reported conflicting results (Xiao et al., 2021). Jia and colleagues calculated a PHRED-CADD score of 23.8 (Jia et al., 2020).

Qiu and colleagues (Qiu et al., 2019) classified the mutation as “pathogenic” according to the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (Richards et al., 2015).

Pathogenicity

Alzheimer's Disease : Likely Pathogenic

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. G111V: Aβ42 levels were similar to wildtype, but Aβ40 levels were reduced resulting in an elevated Aβ42/Aβ40 ratio.

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: 22 Feb 2022

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References

Paper Citations

Qiu Q, Jia L, Wang Q, Zhao L, Jin H, Li T, Quan M, Xu L, Li B, Li Y, Jia J. Identification of a novel PSEN1 Gly111Val missense mutation in a Chinese pedigree with early-onset Alzheimer's disease. Neurobiol Aging. 2020 Jan;85:155.e1-155.e4. Epub 2019 May 31 PubMed.
Jia L, Fu Y, Shen L, Zhang H, Zhu M, Qiu Q, Wang Q, Yan X, Kong C, Hao J, Wei C, Tang Y, Qin W, Li Y, Wang F, Guo D, Zhou A, Zuo X, Yu Y, Li D, Zhao L, Jin H, Jia J. PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. 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.
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.

Mutations

PSEN1 G111V

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