Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73217137 C>T
Position: (GRCh37/hg19):Chr14:73683845 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTT to TTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation was identified by whole exome sequencing in a family with suspected autosomal-dominant Kufs disease (adult-onset neuronal ceroid lipofuscinoses). Five affected individuals were described over three generations. The mutation was found in three affected siblings and was absent from the unaffected mother indicating segregation with disease. The mutation was also absent from the gnomAD database (gnomAD, v2.1.1, Aug 2021).

The proband developed progressive dementia and ataxia at the age of 32. His fine motor coordination became impaired and he developed remote memory deficits. He developed slurred speech and an unsteady gait. Later he developed spastic paraparesis and died at age 36 from aspiration pneumonia. A skin biopsy showed lipofuscin containing phagocytic cells suggestive of neuronal ceroid lipofuscinoses, but his neuropathology was consistent with AD. The proband had two affected brothers with similar disease manifestations (onset at ages 29 and 30) and an affected father with onset at age 28 (Dolzhanskaya et al., 2014).

Neuropathology

Neuropathology consistent with AD, including neuritic amyloid plaques and neurofibrillary tangles. Hirano bodies and granulovacuolar degeneration were noted in the hippocampus (Dolzhanskaya et al., 2014).

Biological Effect

Although the biological effect of this mutation is unknown, in silico analysis indicated that it may affect the folding free energy and flexibility of the presenilin-1 protein (Dolzhanskaya et al., 2014), and multiple algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted it was damaging (Xiao et al., 2021). Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that L381 forms part of one of two PSEN1 β-strands induced by APP binding. These strands, together with an APP β-strand, form a hybrid, three-stranded β–sheet that appears to be indispensable for APP cleavage (Zhou et al., 2019; Jan 2019 news).

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.

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. L381F: 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.

PP1-S

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. L381F: At least one family with >=3 affected carriers and >=1 unaffected noncarriers.

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

News Citations

Paper Citations

Dolzhanskaya N, Gonzalez MA, Sperziani F, Stefl S, Messing J, Wen GY, Alexov E, Zuchner S, Velinov M. A novel p.Leu(381)Phe mutation in presenilin 1 is associated with very early onset and unusually fast progressing dementia as well as lysosomal inclusions typically seen in Kufs disease. J Alzheimers Dis. 2014;39(1):23-7. 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.
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.

Mutations

PSEN1 L381F

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