PSEN2 S130L - GET-Evidence



(PSEN2 Ser130Leu)

Short summary

Occasional observations report this in patients with Alzheimer’s Disease (AD), and other variants in this gene cause early-onset AD. One group speculates an association with dilated cardiomyopathy. However, a functional study found no abnormal behavior (Walker et al.) and none of these studies showed statistically significant associations of the variant with either of these diseases.

Variant evidence
Computational 2

Polyphen 2 predicts damaging effect, other variants in this disease associated with early onset Alzheimer’s Disease

Functional -1

No aberrant functional effect seen in amyloid beta and c-terminal fragment assays.

See Walker ES et al. 2005 (15663477).


No statistically significant evidence.

See Li D et al. 2006 (17186461), Tomaino C et al. 2007 (17345043), Lohmann E et al. 2012 (22503161).

Familial -
Clinical importance
Severity 3

all cases late-onset

Treatability 1
Penetrance 2

penetrance unclear



Low clinical importance, Uncertain pathogenic

(The "low clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary


Allele frequency

  • T @ chr1:227073271: 0.1% (9/10758) in EVS
  • Frequency shown in summary reports: 0.1% (9/10758)


Tedde A, Nacmias B, Ciantelli M, Forleo P, Cellini E, Bagnoli S, Piccini C, Caffarra P, Ghidoni E, Paganini M, Bracco L, Sorbi S. Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed PMID: 14623725.


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 PMID: 15663477.

Introducing this and other PSEN2 variants in plasmids, they found no elevated amyloid beta 42 levels and normal c-terminal fragment levels.

Li D, Parks SB, Kushner JD, Nauman D, Burgess D, Ludwigsen S, Partain J, Nixon RR, Allen CN, Irwin RP, Jakobs PM, Litt M, Hershberger RE. Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am J Hum Genet. 2006 Dec;79(6):1030-9. Epub 2006 Oct 24. PubMed PMID: 17186461; PubMed Central PMCID: PMC1698711.

315 patients with dilated cardiomyopathy (DCM) were screened for variants in PSEN1 and PSEN2 — because these are expressed in the heart, and the authors speculate these genes may also be associated with dilated cardiomyopathy (in addition to AD). 132 were familial DCM cases, and 183 with idiopathic or possibly familial DCM. This variant (PSEN2 S130L) was found in two families, and not found in 413 controls (206 white, 207 african american; both families with S130L were white).

Results reported by Li et al aren’t statistically significant (p = 0.187 with Fisher’s Exact for their reported cases vs. controls) and have no significant difference from EVS data.

Tomaino C, Bernardi L, Anfossi M, Costanzo A, Ferrise F, Gallo M, Geracitano S, Maletta R, Curcio SA, Mirabelli M, Colao R, Frangipane F, Puccio G, Calignano C, Muraca MG, Paonessa A, Smirne N, Leotta A, Bruni AC. Presenilin 2 Ser130Leu mutation in a case of late-onset "sporadic" Alzheimer's disease. J Neurol. 2007 Mar;254(3):391-3. Epub 2007 Mar 7. PubMed PMID: 17345043.

A case report of a single patient with apparently sporadic late-onset AD, who had molecular screening of known familial AD genes. This variant was found; the authors test 110 controls and found none carrying the variant.

The authors equivocate regarding the pathogenicity of this variant, noting that it does not map to a transmembrane domain (different to other reported pathogenic PSEN2 mutations), and speculate that it could have a different disruptive effect.

None of the data in this paper showed any statistically significant associations for this variant in cases and controls.

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. doi: 10.1016/j.neurobiolaging.2012.02.020. Epub 2012 Apr 13. PubMed PMID: 22503161.

A study of mostly Turkish families. One patient in a screen of 98 families carried this variant; this patient had been diagnosed with Alzheimers Disease, age at onset 77 years. Overall, 56 families were diagnosed with AD, 31 with mild cognitive impairment, and the remainder with frontotemporal dementia (8), Lewy body disease (4), Parkinson disease with dementia (3), or atypical or mixed types of dementia (4). The study examined APP (exons 16 and 17), PSEN1 (exons 3–12), and PSEN2 (exons 3–12), as well as the flanking intronic sequences.

The authors note that segregation with the disease in this family could not be established. They note that all variant carriers reported to date had late onset AD (72-81 years) and slow progressing cognitive impairment. They classify the variant as “probably pathogenic”.

EVS data describes 9 out of 5370 samples as carrying this variant heterozygously (0.2% of individuals). We don’t know the phenotypes of these individuals, but Lohmann et al’s observation has no statistically significant enrichment compared to this population.


Other external references

  • Score: 0.933 (probably damaging)
    Web search results (6 hits -- see all)
  • OMIM: 600759
    They observed that the absence of Psen1 or both Psen1 and Psen2 in mice resulted in reduced PEN2 levels. ... PSEN2 gene, predicting to result in an ser130-to-leu (S130L) amino ...
  • ARTICLE Mutations of Presenilin Genes in Dilated ...
    ... was altered in cultured skin fibroblasts from PSEN1 and PSEN2 mutation carriers. ... data indicate that PSEN1 and PSEN2 mutations are associated with DCM and heart ...
  • Mutations of Presenilin Genes in Dilated Cardiomyopathy and ...
    The PSEN2 mutation showed partial penetrance, milder disease, and a more ... These data indicate that PSEN1 and PSEN2 mutations are associated with DCM and ...
  • Abstracts Involving Washington University Investigators
    Dynamics of Amyloid Associated Neuritic Dystrophy Before and After ... Brunkan Endoproteolysis of Presenilin-1 Is an Intramolecular Autocatalytic Event ... ABSTRACT BOOKLET.pdf

Other in silico analyses

  • NBLOSUM100 score = 6
  • GET-Evidence autoscore = 6

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Gene search

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