PSEN1
presenilin 1, the group of Peptidase family A22
Basic information
Region (hg38): 14:73136418-73223691
Previous symbols: [ "AD3" ]
Links
Phenotypes
GenCC
Source:
- Alzheimer disease 3 (Strong), mode of inheritance: AD
- semantic dementia (Strong), mode of inheritance: AD
- Pick disease (Strong), mode of inheritance: AD
- Alzheimer disease 3 (Strong), mode of inheritance: AD
- early-onset autosomal dominant Alzheimer disease (Supportive), mode of inheritance: AD
- familial isolated dilated cardiomyopathy (Supportive), mode of inheritance: AD
- behavioral variant of frontotemporal dementia (Supportive), mode of inheritance: AD
- dilated cardiomyopathy 1U (Limited), mode of inheritance: AD
- acne inversa, familial, 3 (Limited), mode of inheritance: AD
- Alzheimer disease 3 (Strong), mode of inheritance: AD
- semantic dementia (Limited), mode of inheritance: AD
- dilated cardiomyopathy (Disputed Evidence), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Cardiomyopathy, dilated 1U | AD | Cardiovascular | Surveillance (eg, with echocardiography), preventive measures and medical management may be helpful to decrease morbidity | Cardiovascular; Dermatologic; Neurologic | 7550356; 7596406; 7585193; 9052708; 9384602; 9521418; 9544835; 11094121; 11389157; 11524469; 12891668; 12668610; 15122701; 16216949; 16033913; 17186461; 20194882; 20929727; 21495993; 21656036 |
| The reported onset of heart failure has been in the adult period (including in young adults), but surveillance and early treatment may be indicated prior to adulthood |
ClinVar
This is a list of variants' phenotypes submitted to
- not provided (40 variants)
- Alzheimer disease 3 (24 variants)
- Acne inversa, familial, 3;Pick disease;Frontotemporal dementia;Alzheimer disease 3 (10 variants)
- Alzheimer disease 3;Frontotemporal dementia;Pick disease;Acne inversa, familial, 3 (9 variants)
- Alzheimer disease 3;Pick disease;Frontotemporal dementia;Acne inversa, familial, 3 (9 variants)
- Alzheimer disease 3;Acne inversa, familial, 3;Frontotemporal dementia;Pick disease (3 variants)
- Acne inversa, familial, 3;Frontotemporal dementia;Pick disease;Alzheimer disease 3 (2 variants)
- Pick disease (2 variants)
- Acne inversa, familial, 3;Pick disease;Alzheimer disease 3;Frontotemporal dementia (2 variants)
- Pick disease;Frontotemporal dementia;Alzheimer disease 3;Acne inversa, familial, 3 (2 variants)
- Alzheimer disease, familial, with spastic paraparesis and unusual plaques (2 variants)
- PSEN1-related disorder (1 variants)
- Alzheimer disease (1 variants)
- Pick disease;Acne inversa, familial, 3;Frontotemporal dementia;Alzheimer disease 3 (1 variants)
- Alzheimer disease 4 (1 variants)
- Abnormality of the nervous system (1 variants)
- Alzheimer disease, familial, 3, with unusual plaques (1 variants)
- Alzheimer disease 3;Acne inversa, familial, 3;Pick disease;Frontotemporal dementia (1 variants)
- Alzheimer disease 3;Spastic paraparesis (1 variants)
- Acne inversa, familial, 3;Pick disease;Dilated cardiomyopathy 1U;Frontotemporal dementia;Alzheimer disease 3 (1 variants)
- Acne inversa, familial, 3;Frontotemporal dementia;Dilated cardiomyopathy 1U;Pick disease;Alzheimer disease 3 (1 variants)
- Familial Alzheimer disease (1 variants)
- Early-onset autosomal dominant Alzheimer disease (1 variants)
- Frontotemporal dementia (1 variants)
- Mental deterioration;Dementia (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the PSEN1 gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 32 | 41 | ||||
| missense | 56 | 47 | 85 | 193 | ||
| nonsense | 1 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| inframe indel | 7 | |||||
| splice donor/acceptor (+/-2bp) | 5 | |||||
| splice region | 1 | 5 | 4 | 1 | 11 | |
| non coding | 70 | 38 | 15 | 123 | ||
| Total | 61 | 49 | 166 | 74 | 20 |
Highest pathogenic variant AF is 0.000125
Variants in PSEN1
This is a list of pathogenic ClinVar variants found in the PSEN1 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 14-73136423-C-T | Early-onset autosomal dominant Alzheimer disease • Dilated Cardiomyopathy, Dominant • Frontotemporal dementia;Alzheimer disease 3;Pick disease;Acne inversa, familial, 3 | Benign/Likely benign (Jan 08, 2024) | ||
| 14-73136478-G-T | Dilated Cardiomyopathy, Dominant • Early-onset autosomal dominant Alzheimer disease | Uncertain significance (Jun 14, 2016) | ||
| 14-73136493-C-A | Dilated Cardiomyopathy, Dominant • Early-onset autosomal dominant Alzheimer disease | Uncertain significance (Jun 14, 2016) | ||
| 14-73136505-T-G | Dilated Cardiomyopathy, Dominant • Early-onset autosomal dominant Alzheimer disease | Uncertain significance (Jun 14, 2016) | ||
| 14-73136518-A-C | Dilated cardiomyopathy 1U • Alzheimer disease 3 | Uncertain significance (Jan 13, 2018) | ||
| 14-73136528-C-T | Dilated cardiomyopathy 1U • Alzheimer disease 3 | Uncertain significance (Jan 13, 2018) | ||
| 14-73136539-C-T | Dilated cardiomyopathy 1U • Alzheimer disease 3 | Uncertain significance (Jan 13, 2018) | ||
| 14-73136796-G-A | Alzheimer disease 3;Frontotemporal dementia;Pick disease;Acne inversa, familial, 3 | Likely benign (Feb 01, 2023) | ||
| 14-73148040-G-A | Dilated cardiomyopathy 1U • Alzheimer disease 3 | Uncertain significance (Jan 13, 2018) | ||
| 14-73148061-A-C | Likely benign (Aug 01, 2022) | |||
| 14-73148082-C-T | Likely benign (Jul 25, 2018) | |||
| 14-73148098-C-T | Dilated cardiomyopathy 1U • Frontotemporal dementia;Pick disease;Acne inversa, familial, 3;Alzheimer disease 3 • Alzheimer disease 3 | Uncertain significance (Feb 24, 2020) | ||
| 14-73148099-G-A | Dilated cardiomyopathy 1U • Alzheimer disease 3 • not specified | Uncertain significance (May 03, 2024) | ||
| 14-73148113-T-TGTCA | Alzheimer disease 3;Frontotemporal dementia;Pick disease;Acne inversa, familial, 3 | Likely benign (Jul 23, 2022) | ||
| 14-73148358-G-A | Benign (Sep 23, 2018) | |||
| 14-73170790-C-T | Frontotemporal dementia;Acne inversa, familial, 3;Pick disease;Alzheimer disease 3 | Likely benign (Jul 09, 2018) | ||
| 14-73170795-A-G | Uncertain significance (Mar 29, 2022) | |||
| 14-73170804-A-G | not specified • Alzheimer disease 3;Frontotemporal dementia;Pick disease;Acne inversa, familial, 3 | Conflicting classifications of pathogenicity (Jul 03, 2023) | ||
| 14-73170805-T-C | not specified | Benign/Likely benign (Oct 01, 2023) | ||
| 14-73170812-C-T | Frontotemporal dementia;Primary degenerative dementia of the Alzheimer type, presenile onset | Uncertain significance (Oct 28, 2019) | ||
| 14-73170813-G-A | Alzheimer disease • Alzheimer disease 3;Pick disease;Frontotemporal dementia;Acne inversa, familial, 3 • Alzheimer disease 3 • Dilated cardiomyopathy 1U | Conflicting classifications of pathogenicity (Dec 04, 2023) | ||
| 14-73170824-AACG-A | Frontotemporal dementia;Pick disease;Acne inversa, familial, 3;Alzheimer disease 3 • PSEN1-related disorder | Uncertain significance (Sep 27, 2023) | ||
| 14-73170827-G-A | not specified | Uncertain significance (Apr 03, 2024) | ||
| 14-73170830-A-G | Uncertain significance (Jan 08, 2024) | |||
| 14-73170832-A-T | Alzheimer disease 3;Frontotemporal dementia;Pick disease;Acne inversa, familial, 3 | Uncertain significance (Mar 06, 2022) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| PSEN1 | protein_coding | protein_coding | ENST00000324501 | 10 | 87274 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.973 | 0.0268 | 125736 | 0 | 12 | 125748 | 0.0000477 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 2.16 | 159 | 256 | 0.621 | 0.0000138 | 3045 |
| Missense in Polyphen | 48 | 119.03 | 0.40325 | 1496 | ||
| Synonymous | -0.441 | 103 | 97.5 | 1.06 | 0.00000540 | 918 |
| Loss of Function | 4.01 | 3 | 24.4 | 0.123 | 0.00000131 | 285 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000206 | 0.000206 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.0000544 | 0.0000544 |
| Finnish | 0.000139 | 0.0000462 |
| European (Non-Finnish) | 0.0000532 | 0.0000527 |
| Middle Eastern | 0.0000544 | 0.0000544 |
| South Asian | 0.00 | 0.00 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:15274632, PubMed:10545183, PubMed:10593990, PubMed:10206644, PubMed:10899933, PubMed:10811883, PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335). Requires the presence of the other members of the gamma-secretase complex for protease activity (PubMed:15274632, PubMed:25043039, PubMed:26280335). Plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (PubMed:9738936, PubMed:10593990, PubMed:10899933, PubMed:10811883). Stimulates cell-cell adhesion via its interaction with CDH1; this stabilizes the complexes between CDH1 (E-cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 and JUP (gamma-catenin) (PubMed:11953314). Under conditions of apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This promotes the disassembly of the complexes between CDH1 and CTNND1, JUP and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby negatively regulates Wnt signaling (PubMed:9738936, PubMed:11953314). Required for normal embryonic brain and skeleton development, and for normal angiogenesis (By similarity). {ECO:0000250|UniProtKB:P49769, ECO:0000269|PubMed:10206644, ECO:0000269|PubMed:10545183, ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:10811883, ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:11953314, ECO:0000269|PubMed:12679784, ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:9738936}.;
- Disease
- DISEASE: Alzheimer disease 3 (AD3) [MIM:607822]: A familial early- onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C- terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. {ECO:0000269|PubMed:10025789, ECO:0000269|PubMed:10090481, ECO:0000269|PubMed:10200054, ECO:0000269|PubMed:10208579, ECO:0000269|PubMed:10439444, ECO:0000269|PubMed:10441572, ECO:0000269|PubMed:10447269, ECO:0000269|PubMed:10533070, ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10644793, ECO:0000269|PubMed:11027672, ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:11710891, ECO:0000269|PubMed:11920851, ECO:0000269|PubMed:12048239, ECO:0000269|PubMed:12058025, ECO:0000269|PubMed:12484344, ECO:0000269|PubMed:12493737, ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:20460383, ECO:0000269|PubMed:22503161, ECO:0000269|PubMed:26145164, ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26549787, ECO:0000269|PubMed:7550356, ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:8634711, ECO:0000269|PubMed:8634712, ECO:0000269|PubMed:8733303, ECO:0000269|PubMed:9172170, ECO:0000269|PubMed:9225696, ECO:0000269|PubMed:9298817, ECO:0000269|PubMed:9384602, ECO:0000269|PubMed:9507958, ECO:0000269|PubMed:9521423, ECO:0000269|PubMed:9719376, ECO:0000269|PubMed:9831473, ECO:0000269|PubMed:9833068, ECO:0000269|Ref.84}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Frontotemporal dementia (FTD) [MIM:600274]: A form of dementia characterized by pathologic finding of frontotemporal lobar degeneration, presenile dementia with behavioral changes, deterioration of cognitive capacities and loss of memory. In some cases, parkinsonian symptoms are prominent. Neuropathological changes include frontotemporal atrophy often associated with atrophy of the basal ganglia, substantia nigra, amygdala. In most cases, protein tau deposits are found in glial cells and/or neurons. {ECO:0000269|PubMed:11094121}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated 1U (CMD1U) [MIM:613694]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:17186461}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Acne inversa, familial, 3 (ACNINV3) [MIM:613737]: A chronic relapsing inflammatory disease of the hair follicles characterized by recurrent draining sinuses, painful skin abscesses, and disfiguring scars. Manifestations typically appear after puberty. {ECO:0000269|PubMed:20929727}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- Neurotrophin signaling pathway - Homo sapiens (human);Alzheimer,s disease - Homo sapiens (human);Wnt signaling pathway - Homo sapiens (human);Notch signaling pathway - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);NOTCH-Core;Alzheimers Disease;Notch Signaling Pathway;Canonical and Non-canonical Notch signaling;Notch Signaling Pathway;Notch Signaling Pathway;Notch;Neutrophil degranulation;Disease;Signal Transduction;generation of amyloid b-peptide by ps1;proteolysis and signaling pathway of notch;segmentation clock;hiv-1 nef: negative effector of fas and tnf;g-secretase mediated erbb4 signaling pathway;Extracellular matrix organization;DroToll-like;Notch;Innate Immune System;Immune System;Signaling by NOTCH1;Signaling by NOTCH2;NOTCH3 Activation and Transmission of Signal to the Nucleus;Signaling by NOTCH3;Signaling by NOTCH4;Signaling by NOTCH;A third proteolytic cleavage releases NICD;NRIF signals cell death from the nucleus;NOTCH2 Activation and Transmission of Signal to the Nucleus;Degradation of the extracellular matrix;Death Receptor Signalling;Regulated proteolysis of p75NTR;p75 NTR receptor-mediated signalling;Notch signaling pathway;Nuclear signaling by ERBB4;Signaling by ERBB4;Constitutive Signaling by NOTCH1 PEST Domain Mutants;Signaling by NOTCH1 PEST Domain Mutants in Cancer;Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants;Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer;Signaling by NOTCH1 in Cancer;Signaling by Receptor Tyrosine Kinases;Diseases of signal transduction;p75(NTR)-mediated signaling;Cell death signalling via NRAGE, NRIF and NADE;Presenilin action in Notch and Wnt signaling;FGF signaling pathway;Syndecan-3-mediated signaling events;Activated NOTCH1 Transmits Signal to the Nucleus
(Consensus)
Recessive Scores
- pRec
- 0.876
Intolerance Scores
- loftool
- 0.00214
- rvis_EVS
- -0.34
- rvis_percentile_EVS
- 30.37
Haploinsufficiency Scores
- pHI
- 0.949
- hipred
- Y
- hipred_score
- 0.729
- ghis
- 0.652
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.964
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Psen1
- Phenotype
- growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype; muscle phenotype; craniofacial phenotype; homeostasis/metabolism phenotype; cellular phenotype; skeleton phenotype; renal/urinary system phenotype; embryo phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; reproductive system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); digestive/alimentary phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; immune system phenotype;
Zebrafish Information Network
- Gene name
- psen1
- Affected structure
- neuron
- Phenotype tag
- abnormal
- Phenotype quality
- increased amount
Gene ontology
- Biological process
- autophagosome assembly;negative regulation of transcription by RNA polymerase II;activation of MAPKK activity;blood vessel development;cell fate specification;somitogenesis;neuron migration;positive regulation of receptor recycling;heart looping;positive regulation of L-glutamate import across plasma membrane;hematopoietic progenitor cell differentiation;astrocyte activation involved in immune response;T cell activation involved in immune response;neural retina development;protein glycosylation;membrane protein ectodomain proteolysis;mitochondrial transport;cellular response to DNA damage stimulus;response to oxidative stress;negative regulation of epidermal growth factor-activated receptor activity;Notch receptor processing;learning or memory;memory;post-embryonic development;protein transport;choline transport;synaptic vesicle targeting;protein processing;cerebral cortex cell migration;Cajal-Retzius cell differentiation;dorsal/ventral neural tube patterning;embryonic limb morphogenesis;positive regulation of protein binding;positive regulation of proteasomal ubiquitin-dependent protein catabolic process;endoplasmic reticulum calcium ion homeostasis;obsolete positive regulation of protein import into nucleus, translocation;amyloid-beta formation;Notch receptor processing, ligand-dependent;intracellular signal transduction;regulation of phosphorylation;positive regulation of phosphorylation;amyloid precursor protein metabolic process;amyloid precursor protein catabolic process;myeloid dendritic cell differentiation;positive regulation of apoptotic process;negative regulation of apoptotic process;positive regulation of catalytic activity;neutrophil degranulation;negative regulation of neuron apoptotic process;skin morphogenesis;positive regulation of transcription, DNA-templated;astrocyte activation;regulation of synaptic plasticity;thymus development;neuron development;skeletal system morphogenesis;brain morphogenesis;epithelial cell proliferation;negative regulation of axonogenesis;synapse organization;positive regulation of coagulation;T cell receptor signaling pathway;neuron apoptotic process;negative regulation of ubiquitin-protein transferase activity;smooth endoplasmic reticulum calcium ion homeostasis;regulation of synaptic transmission, glutamatergic;regulation of resting membrane potential;regulation of canonical Wnt signaling pathway;positive regulation of dendritic spine development;calcium ion transmembrane transport;modulation of age-related behavioral decline;cell-cell adhesion;cellular response to amyloid-beta;negative regulation of core promoter binding;negative regulation of low-density lipoprotein receptor activity;positive regulation of amyloid fibril formation;neuron projection maintenance;negative regulation of ubiquitin-dependent protein catabolic process;negative regulation of apoptotic signaling pathway
- Cellular component
- Golgi membrane;kinetochore;nucleus;nuclear outer membrane;mitochondrion;mitochondrial inner membrane;endoplasmic reticulum;endoplasmic reticulum membrane;smooth endoplasmic reticulum;rough endoplasmic reticulum;Golgi apparatus;centrosome;plasma membrane;integral component of plasma membrane;cell cortex;cell surface;membrane;integral component of membrane;aggresome;cell junction;growth cone;neuromuscular junction;nuclear membrane;protein-containing complex;ciliary rootlet;azurophil granule membrane;neuronal cell body;dendritic shaft;membrane raft;gamma-secretase complex;integral component of presynaptic membrane
- Molecular function
- endopeptidase activity;aspartic-type endopeptidase activity;calcium channel activity;protein binding;beta-catenin binding;PDZ domain binding;aspartic endopeptidase activity, intramembrane cleaving;cadherin binding