Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226885545 A>C
Position: (GRCh37/hg19):Chr1:227073246 A>C
dbSNP ID: rs63749851
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACG to CCG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6

Findings

This mutation was first identified in a patient diagnosed with probable early onset Alzheimer's disease. The patient, who was identified as Patient 6 in the study, was from Germany and had a positive family history of dementia. Her mother and maternal grandmother had died at 48 and 51 years old, respectively. The patient had disease onset at age 46 (Finckh et al., 2000).

This mutation was identified in a second, presumably unrelated, German patient who also had a family history of dementia. The patient, identified as P. 48, had disease onset at age 50. The patient's father and paternal uncle also had been diagnosed with dementia (Finckh et al., 2005).

In addition, this variant was identified in a screen of patients with early onset AD from 28 French hospitals (Lanoiselée et al., 2017). Families were included when at least two first-degree relatives, spanning two generations, suffered from early onset AD with an age of onset of 65 years or younger. Age at onset in this pedigree, which included one affected mutation carrier, ranged from 45 to 47 years, and disease duration ranged from two to seven years. 

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

Neuropathology

Unknown.

Biological Effect

When transfected into fibroblasts lacking endogenous PSEN1 or PSEN2, the T122P mutation did not affect steady-state levels of the proteolytic products PSEN2-CTF and PSEN2-NTF compared with wild-type PSEN2. When co-transfected with APP carrying the Swedish mutation, the T122P mutation produced elevated levels of Aβ42 and increased the Aβ42/Aβ40 ratio (Walker et al., 2005).

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.

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References

Paper Citations

1. Finckh U, Müller-Thomsen T, Mann U, Eggers C, Marksteiner J, Meins W, Binetti G, Alberici A, Hock C, Nitsch RM, Gal A. High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet. 2000 Jan;66(1):110-7. PubMed.
2. Finckh U, Kuschel C, Anagnostouli M, Patsouris E, Pantes GV, Gatzonis S, Kapaki E, Davaki P, Lamszus K, Stavrou D, Gal A. Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
3. Lanoiselée HM, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, Richard AC, Pasquier F, Rollin-Sillaire A, Martinaud O, Quillard-Muraine M, de la Sayette V, Boutoleau-Bretonniere C, Etcharry-Bouyx F, Chauviré V, Sarazin M, le Ber I, Epelbaum S, Jonveaux T, Rouaud O, Ceccaldi M, Félician O, Godefroy O, Formaglio M, Croisile B, Auriacombe S, Chamard L, Vincent JL, Sauvée M, Marelli-Tosi C, Gabelle A, Ozsancak C, Pariente J, Paquet C, Hannequin D, Campion D, collaborators of the CNR-MAJ project. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
4. Walker ES, Martinez M, Brunkan AL, Goate A. Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem. 2005 Jan;92(2):294-301. PubMed.

Other Citations

1. Swedish mutation

Further Reading

Learn More

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database