Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: BS1, BS2, BS3, BS4, BP4
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Position: (GRCh38/hg38):Chr1:226888112 A>G
Position: (GRCh37/hg19):Chr1:227075813 A>G
dbSNP ID: rs61757781
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATG to GTG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 7

Findings

This PSEN2 variant has been reported in several individuals with Alzheimer's disease or frontotemporal dementia, as well as some healthy family members. Currently, there is no evidence that it segregates with disease, and in fact, it has been shown not to segregate with disease in one family. The variant is present in the gnomAD variant database at a frequency of 0.00059, including 165 heterozygotes of different ancestries and one South Asian homozygote (gnomAD v2.1.1, Nov 2021). Some researchers have proposed it has low penetrance or is a risk modifier.

This variant was first reported in 2008, but details were not available (Clarimón et al., 2008; Andreoli et al., 2008). It was subsequently reported in a woman who developed Alzheimer’s disease at age 54 and was described by the authors as possibly pathogenic (Guerreiro et al., 2010).

A later study found this variant in a family with a history of late-onset AD, but it did not segregate with disease. Specifically, M174V was detected in one affected individual and three healthy family members. In addition, some affected members of the family were not carriers, arguing against pathogenicity (Cruchaga et al., 2012).

Another study reported the M174V mutation in two unrelated Turkish individuals, both exhibiting symptoms consistent with frontotemporal dementia (Lohmann et al., 2012). One patient developed symptoms at age 52, starting with progressive non-fluent aphasia, followed by postural instability, gait disturbance, and dystonia in the right leg. There was a history of neurological disease in the family. The proband's father had Parkinson’s disease and his maternal grandfather died at age 38 from an unspecified neurological disease. His parents were first cousins. The proband's sister was also a mutation carrier. She was healthy at the age of 36.

The second Turkish patient developed changes in mood and personality, notably increased aggression, at age 60. Progressive deficits in speech and attention followed. He was described as having a “frontal syndrome” characterized by a deficit in executive function. His mother had clinically significant memory problems and died at age 64 from a stroke. Segregation with disease could not be determined.

A study based in the U.S. also reported a woman who carried the mutation and had a family history of dementia (Wojtas et al., 2012). Her first clinical symptom, memory loss, emerged at age 45. Of note, she was homozygous for the APOE4 allele.

In addition, the mutation was identified in a Spanish individual with AD confirmed by positive cerebrospinal fluid AD biomarkers (Ramos-Campoy et al., 2020). There was no family history of AD. Age at onset was 50 years. Of note, this patient also had a missense variant in the ABCA7 gene (S1629L) which had not been reported before.

Two additional carriers were reported in an Italian study of 102 patients with early onset AD (Bartoletti-Stella et al., 2022). Both carriers had a moderate family history of disease, one having a single first- or second-degree family member affected by early onset AD, and the other having a single first- or second-degree family member affected with late-onset AD.

Neuropathology

Neuropathological data are unavailable. Imaging in one affected carrier showed bilateral atrophy in the parietal lobe and hypoperfusion in temporoparietal regions (Guerreiro et al., 2010). Imaging in the two Turkish individuals with FTD showed cortical and anterior temporal lobe atrophy in one individual and frontal atrophy and hypometabolism in the frontotemporoparietal regions in the other patient (Lohmann et al., 2012).

Biological Effect

A cellular assay using mouse neuroblastoma cells expressing the mutant protein showed similar amounts of Aβ42 and Aβ40 secretion as in cells expressing wild-type PSEN2, with a modest decrease of Aβ40 secretion and no significant alteration of Aβ42 or the ratio of Aβ42/Aβ40 (Hsu et al., 2020).

M174V is located in the third transmembrane domain of PSEN2. The residue is not conserved in PSEN1. Although it was predicted benign by in silico algorithms PolyPhen-2 and SIFT (Cruchaga et al., 2012; Lohmann et al., 2012, Hsu et al., 2020), it was predicted deleterious by LRT, Mutation Taster, FATHMM, Radial SVM, and LR (Ramos-Campoy et al., 2020). Its PHRED-scaled CADD score, which integrates diverse information in silico, was high, but did not reach the commonly used deleteriousness threshold of 20 (18.11; CADD v.1.6, Jan 2023).

Ramos-Campoy and colleagues suggested the variant may be a risk modifier or have low penetrance (Ramos-Campoy et al., 2020). Similarly, Bartoletti-Stella and co-workers classified it as a contributor to disease, taking into account the familial history of the carriers and the frequency of the variant in their cohort (0.02) compared with that in the non-Finnish population of the gnomAD variant database (0.00034) (Bartoletti-Stella et al., 2022). 

Pathogenicity

Alzheimer's Disease : Benign*

*Some evidence suggests this variant may be a risk modifier, a classification not included in the ACMG-AMP guidelines.

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. Clarimón J, Guerreiro R, Lleó A, Guardia C, Blesa F, Gómez-Isla T, Boada M, Bullido MJ, Ferrer I, Martínez-Lage P, Masdeu J, Molina L, Molinuevo JL, Pastor P, Pérez-Tur J, Rey MJ, Sánchez-Valle R, Tàrraga L, Valdivieso F, Singleton A, Hardy J. Genetic screening in a large cohort of early-onset Alzheimer's disease patients from Spain: novel mutations in the amyloid precursor protein and presenilines. Alzheimers Demen. 2008 Jul;4(4 Suppl):T583.
2. Andreoli V, Trecroci F, La Russa A, Di Palma G, Quattrone A, Cittadella R. Gene symbol: PSEN2. Disease: Alzheimer disease. Hum Genet. 2008 Oct;124(3):304. PubMed.
3. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
4. Cruchaga C, Haller G, Chakraverty S, Mayo K, Vallania FL, Mitra RD, Faber K, Williamson J, Bird T, Diaz-Arrastia R, Foroud TM, Boeve BF, Graff-Radford NR, St Jean P, Lawson M, Ehm MG, Mayeux R, Goate AM, NIA-LOAD/NCRAD Family Study Consortium. Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PLoS One. 2012;7(2):e31039. Epub 2012 Feb 1 PubMed.
5. Lohmann E, Guerreiro RJ, Erginel-Unaltuna N, Gurunlian N, Bilgic B, Gurvit H, Hanagasi HA, Luu N, Emre M, Singleton A. Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
6. Wojtas A, Heggeli KA, Finch N, Baker M, Dejesus-Hernandez M, Younkin SG, Dickson DW, Graff-Radford NR, Rademakers R. C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic. Am J Neurodegener Dis. 2012;1(1):107-18. Epub 2012 May 16 PubMed.
7. Ramos-Campoy O, Antonell A, Falgàs N, Balasa M, Borrego-Écija S, Rodríguez-Santiago B, Datta D, Armengol L, Fernández-Villullas G, Bosch B, Olives J, Muñoz-García C, Castellví M, Tort-Merino A, Sánchez-Valle R, Lladó A. Screening of dementia genes by whole-exome sequencing in Spanish patients with early-onset dementia: likely pathogenic, uncertain significance and risk variants. Neurobiol Aging. 2020 Sep;93:e1-e9. Epub 2020 Feb 18 PubMed.
8. Bartoletti-Stella A, Tarozzi M, Mengozzi G, Asirelli F, Brancaleoni L, Mometto N, Stanzani-Maserati M, Baiardi S, Linarello S, Spallazzi M, Pantieri R, Ferriani E, Caffarra P, Liguori R, Parchi P, Capellari S. Dementia-related genetic variants in an Italian population of early-onset Alzheimer's disease. Front Aging Neurosci. 2022;14:969817. Epub 2022 Sep 5 PubMed.
9. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

Further Reading