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):Chr14:73198051 C>T
Position: (GRCh37/hg19):Chr14:73664759 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCG to TCG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This variant was found in a Brazilian family spanning three generations with three members affected by early onset Alzheimer’s disease (Takada et al., 2022). Mean age at onset was 48.5 years. The proband’s first symptom was memory loss at age 45 followed by geographic disorientation. Both verbal and visual recall were impaired, while semantic and phonemic fluency were relatively preserved. Only the proband was genotyped.

The variant was absent from the variant databases gnomAD and the exome variant server, and was not reported in the ClinVar database.

Neuropathology
Neuropathological data are unavailable.

Biological Effect
An assay using neuroblastoma N2A cells lacking endogenous presenilin genes and expressing the P264S mutation revealed a large increase in the Aβ42/Aβ40 ratio. Both Aβ40 and Aβ42 levels were dramatically decreased, with Aβ40 being nearly undetectable (Takada et al., 2022).

L395 is highly conserved between PSEN1 and PSEN2 and is near the aspartate residues that regulate catalytic activity. Moreover, L264S’s PHRED-scaled CADD score (28.4), which integrates diverse information in silico, was above 20, suggesting a deleterious effect. In addition, another variant at this position, P264L, has been classified as pathogenic. The authors noted that two pathogenicity classification systems based on the ACMG guidelines classified this variant as pathogenic or likely pathogenic, and the algorithm described by Hsu et al., 2018 classified it as pathogenic.

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-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. P264S: Aβ42/Aβ40 ratio increased, but production of both peptides decreased.

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. P264S: 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 Jan 2023

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References

Paper Citations

Takada LT, Aláez-Verson C, Burgute BD, Nitrini R, Sosa AL, Castilhos RM, Chaves MF, Longoria EM, Carrillo-Sánchez K, Brucki SM, Flores-Lagunes LL, Molina C, Olivares MJ, Ziegemeier E, Petranek J, Goate AM, Cruchaga C, Renton AE, Fernández MV, Day GS, McDade E, Bateman RJ, Karch CM, Llibre-Guerra JJ, Dominantly Inherited Alzheimer Network. Discovery and validation of dominantly inherited Alzheimer's disease mutations in populations from Latin America. Alzheimers Res Ther. 2022 Aug 5;14(1):108. 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.
Hsu S, Gordon BA, Hornbeck R, Norton JB, Levitch D, Louden A, Ziegemeier E, Laforce R Jr, Chhatwal J, Day GS, McDade E, Morris JC, Fagan AM, Benzinger TL, Goate AM, Cruchaga C, Bateman RJ, Dominantly Inherited Alzheimer Network (DIAN), Karch CM. Discovery and validation of autosomal dominant Alzheimer's disease mutations. Alzheimers Res Ther. 2018 Jul 18;10(1):67. PubMed.

Mutations

PSEN1 P264S

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