Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM4
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659506_73659508 --->ATT
dbSNP ID: NA
Coding/Non-Coding: Coding
Codon Change: --- to ATT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This variant was identified in a 45-year-old Chinese man with early onset Alzheimer’s disease (Liang et al., 2023). His symptoms, emerging at age 43, included memory loss, disorientation, and executive dysfunction. A year after onset, he suffered from paranoia, apathy, and irritability. The man was homozygous for the APOE3 allele. He had no family history of disease. His parents died from heart disease and lung cancer before age 65.

This variant was absent from several variant databases, including ESP6500, gnomAD, and ExAC.

Neuropathology
Neuropathological data are unavailable, but brain MRI revealed hippocampal atrophy and ventricular enlargement (Liang et al., 2023). Moreover, PET showed prominent amyloid deposition in frontal, temporal, parietal, and occipital cortices.

Biological Effect
The biological effect of this variant is unknown. However, L235 is evolutionarily conserved (Liang et al., 2023) and missense mutations at this site, L235P and L235V, have been classified by Alzforum as pathogenic and likely pathogenic, respectively. Liang and colleagues classified L235dup as likely pathogenic/pathogenic based on the ACMG-AMP guidelines (Richards et al., 2015).

Functional Consequences

Unknown.

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.

PM4-P

Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. L235dup: SIngle amino acid gain.

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

Last Updated: 02 Aug 2023

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References

Mutations Citations

Paper Citations

Liang Z, Wu Y, Li C, Liu Z. Clinical and genetic characteristics in a central-southern Chinese cohort of early-onset Alzheimer's disease. Front Neurol. 2023;14:1119326. Epub 2023 Mar 27 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 L235dup

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