Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198076 T>A
Position: (GRCh37/hg19):Chr14:73664784 T>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTT to GAT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in an Iraqi man with a family history of early onset dementia suggesting autosomal dominant inheritance (Mengel et al., 2019). Nine family members of the proband’s family, spanning three generations, developed cognitive deterioration between age 40 and 45, leading to death at 45 to 52 years. At age 46, the proband presented with language impairments, having lost his ability to communicate in his second language a few months earlier, and having trouble finding words in his native tongue, as well as expressing phonematic and semantic paraphrasia. He was also disoriented in time and space, and suffered from short-term memory loss. At age 51, the proband was unable to speak or follow simple instructions and was mostly bedridden.
Based on the evolution of cognitive symptoms and the mutation type, the authors provided a tentative diagnosis of a logopenic variant of AD.

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

Neuropathology
Neuropathological data are unavailable, but MRI revealed frontotemporal atrophy, with a generalized reduction in brain volume and minor atrophy of the temporal lobe and hippocampus. AD biomarkers in cerebrospinal fluid, including Aβ42, Aβ40, tau and phosphorylated tau, were in the normal range.

Biological Effect
When overexpressed in PSEN1/2 double knockout HEK293 cells, the mutant increased the ratio of Aβ42/Aβ40 in the culture medium, but not to the extent that a previously reported mutant at the same position, V272A, did. The V272 position is conserved between PSEN1 and PSEN2, but is not in a transmembrane domain (Jimenez-Escrig et al., 2004). 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 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.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

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.

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: 28 Feb 2022

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References

Mutations Citations

Paper Citations

Mengel D, Liu L, Yamamoto R, Zülow S, Deuschl C, Hermann DM, Zerr I, Selkoe DJ, Dodel R. A novel V272D presenilin mutation associated with logopenia, disorientation, and apraxia in an autosomal-dominant Alzheimer's disease family. Neurobiol Aging. 2020 Jan;85:154.e5-154.e7. Epub 2019 Aug 7 PubMed.
Jimenez-Escrig A, Rabano A, Guerrero C, Simon J, Barquero MS, Güell I, Ginestal RC, Montero T, Orensanz L. New V272A presenilin 1 mutation with very early onset subcortical dementia and parkinsonism. Eur J Neurol. 2004 Oct;11(10):663-9. 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 V272D

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