Overview

Pathogenicity: Alzheimer's Disease : Benign, Frontotemporal Dementia : Not Classified
ACMG/AMP Pathogenicity Criteria: BS1, BS2, BS3, BS4, BP4
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia, Parkinson's Disease Dementia
Position: (GRCh38/hg38):Chr1:226883748 G>A
Position: (GRCh37/hg19):Chr1:227071449 G>A
dbSNP ID: rs58973334
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to CAC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 5

Findings

The R62H variant has been found in people with a variety of neurodegenerative diseases (e.g., Alzheimer's disease, frontotemporal dementia, and Parkinson's disease), as well as in healthy controls. In the ExAC variant database, it is present at a 0.009890 frequency, but the frequency is higher in some populations, reaching nearly 4 percent in Africans (ExAC v.1.0, Oct 2020). It does not segregate with disease in the families for which data are available, and is therefore not thought to be pathogenic. Although R62H does not appear to cause familial disease, it may be a disease modifier. After correcting for APOE genotype, AD patients carrying the R62H variant were found to have an earlier age of onset than non-carriers (71 versus 75 years) (Cruchaga et al., 2012).

This variant was first reported in a patient with apparently sporadic Alzheimer's disease who developed symptoms at age 62 (Cruts et al., 1998). It was later found in a patient with late-onset Alzheimer's, but it did not segregate with disease within the family (Sleegers et al., 2004).

A large number of control individuals were later found to carry the R62H variant, suggesting it may be a benign polymorphism. Specifically, the R62H variant was found in 20 African individuals, leading the authors to speculate that it may be a relatively common polymorphism in some African populations (Guerreiro et al., 2010).

This variant was also found in a patient diagnosed with frontotemporal dementia. The patient was 31 years old when she began to experience behavioral disturbances and personality changes. The variant did not segregate with disease; it was found in the patient's cognitively healthy mother but was absent in an affected sibling (Gallo et al., 2010).

The variant was also found in a Turkish man with a family history of AD. The proband developed symptom onset at age 63 and developed symptoms of parkinsonism. The reported pedigree shows that his mother and maternal grandmother were also affected by dementia with apparent autosomal-dominant transmission. Segregation with disease could not be determined due to lack of DNA from family members (Lohmann et al., 2012).

This variant was also found in an individual with idiopathic Parkinson's disease with dementia (Schulte et al., 2015). The patient first developed symptoms of bradykinesia at age 81 and had a three-year disease duration. Other symptoms included rigidity and postural instability. The PD phenotype in this individual is considered unlikely to be attributable to the presence of this variant.

In addition, this variant was found in one out of 72 individuals with AD. There was no family history of AD, and the clinical details related to this case were not reported (Frigerio et al., 2015).

The variant was also reported in a family of the Chinese Familial Alzheimer’s Disease Network, including a total of four affected carriers, three diagnosed with AD and one with mild cognitive impairment  (Jia et al., 2020). Three carriers experienced disease onset in their early 70s, however, the proband's AD onset occurred at age 45. Two of the carriers with AD age at onset of 70 carried one APOE4 allele, while the proband and another carrier were APOE3 homozygotes. 

Neuropathology

Neuropathological data are unavailable. However, cerebrospinal fluid biomarkers from two carriers suffering from AD suggest variability. Whereas one carrier, with an APOE3/3 genotype, had increased levels of Aβ40, Aβ42, and Aβ43, with an Aβ42/Aβ40 ratio in the normal range, another carrier, with an APOE3/4 genotype, had reduced levels of the Aβ40, Aβ42, and Aβ43, with a reduced Aβ42/Aβ40 ratio (Perrone et al., 2020). In both cases, sAPPα, and sAPPβ were reduced. Also, whereas the APOE3/3 carrier of the R62H variant had moderately increased levels of tau and normal levels of phospho-tau, the APOE3/4 carrier of the R62H variant had robustly elevated levels of both tau and phospho-tau. 

Biological Effect

 As described above, CSF levels of Aβ peptides in carriers of this mutation are variable. When transfected into fibroblasts lacking endogenous PSEN1 or PSEN2, the R62H variant 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 R62H mutation did not affect Aβ42 levels or the Aβ42/Aβ40 ratio (Walker et al., 2005). Similar results were seen in transfected HEK293 cells (To et al., 2006) and mouse neuroblastoma cells (Hsu et al., 2020). The R62 residue, located in the N-terminal of PSEN2, is conserved between PSEN1 and PSEN2 (it is R60 in PSEN1).

In silico, the R62H variant is predicted "benign" by PolyPhen and "tolerated" by SIFT (Hsu et al., 2020), and consistently, it has a PHRED-scaled CADD score of only 13 (CADD v.1.6, Nov 2021). It has been classified as not pathogenic according to the algorithm proposed by Guerreiro et al., 2010 (Lohmann et al., 2012; Hsu et al., 2020).

Pathogenicity

Alzheimer's Disease : Benign*

*This variant may be a disease 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. 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.
2. Cruts M, van Duijn CM, Backhovens H, Van den Broeck M, Wehnert A, Serneels S, Sherrington R, Hutton M, Hardy J, St George-Hyslop PH, Hofman A, Van Broeckhoven C. Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998 Jan;7(1):43-51. PubMed.
3. Sleegers K, Roks G, Theuns J, Aulchenko YS, Rademakers R, Cruts M, van Gool WA, Van Broeckhoven C, Heutink P, Oostra BA, van Swieten JC, van Duijn CM. Familial clustering and genetic risk for dementia in a genetically isolated Dutch population. Brain. 2004 Jul;127(Pt 7):1641-9. Epub 2004 May 6 PubMed.
4. 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.
5. Gallo M, Tomaino C, Puccio G, Frangipane F, Curcio SA, Bernardi L, Geracitano S, Anfossi M, Mirabelli M, Colao R, Vasso F, Smirne N, Maletta RG, Bruni AC. Novel MAPT Val75Ala mutation and PSEN2 Arg62Hys in two siblings with frontotemporal dementia. Neurol Sci. 2010 Feb;31(1):65-70. Epub 2009 Sep 19 PubMed.
6. 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.
7. Schulte EC, Fukumori A, Mollenhauer B, Hor H, Arzberger T, Perneczky R, Kurz A, Diehl-Schmid J, Hüll M, Lichtner P, Eckstein G, Zimprich A, Haubenberger D, Pirker W, Brücke T, Bereznai B, Molnar MJ, Lorenzo-Betancor O, Pastor P, Peters A, Gieger C, Estivill X, Meitinger T, Kretzschmar HA, Trenkwalder C, Haass C, Winkelmann J. Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. Eur J Hum Genet. 2015 Jan 21; PubMed.
8. Jia L, Fu Y, Shen L, Zhang H, Zhu M, Qiu Q, Wang Q, Yan X, Kong C, Hao J, Wei C, Tang Y, Qin W, Li Y, Wang F, Guo D, Zhou A, Zuo X, Yu Y, Li D, Zhao L, Jin H, Jia J. PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
9. Perrone F, Bjerke M, Hens E, Sieben A, Timmers M, De Roeck A, Vandenberghe R, Sleegers K, Martin JJ, De Deyn PP, Engelborghs S, van der Zee J, Van Broeckhoven C, Cacace R, BELNEU Consortium. Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108. PubMed.
10. 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.
11. To MD, Gokgoz N, Doyle TG, Donoviel DB, Knight JA, Hyslop PS, Bernstein A, Andrulis IL. Functional characterization of novel presenilin-2 variants identified in human breast cancers. Oncogene. 2006 Jun 15;25(25):3557-64. PubMed.
12. 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.

Other Citations

1. Frigerio et al., 2015

External Citations

1. ExAC v.1.0, Oct 2020

Further Reading