LYST
protein-codinglysosomal trafficking regulator, the group of WD repeat domain containing|BEACH domain containing |MicroRNA protein coding host genes
Gene summary
This gene encodes a protein that regulates intracellular protein trafficking in endosomes, and may be involved in pigmentation. Mutations in this gene are associated with Chediak-Higashi syndrome, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants, though the full-length nature of some of these variants has not been determined. [provided by RefSeq, Apr 2013]
- CHS1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~222.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0008963
Submitter: ClinGen
*LYST* was first reported in relation to Autosomal Recessive Chediak-Higahsi syndrome in 1996 (Nagle et al, PMID: 8896560). At least 50 unique variants, including nonsense, frameshift, missense, deletion and duplication variants have been reported to cause disease in humans, in ClinVar. The exact function of the *LYST* is not completely understood, but is involved in regulating intracellular protein trafficking in endosomes. Chediak-Higahsi syndrome is characterized by partial oculocutaneous albinism, immunodeficiency, and a mild bleeding tendency. Some individuals develop the accelerated phase, or hemophagocytic lymphohistiocytosis, which can be life-threatening (Toro et al, GeneReviews). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 12 Points Variants in this gene have been reported in at least 9 probands in 7 publications (PMIDs: 8896560, 9215680, 31906877, 9215679, 26499269, 24112114, 28145517). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is biallelic loss of function (Ajitkumar & Ramphul, 2019). Summary of Experimental Data: 4.5 Points This gene-disease association is supported by a number of animal models and in vitro functional assays. Chediak-Higashi syndrome arises spontaneously in many animals, including the beige/grey mice, American mink and Japanese black cattle, due to a natural defect in the Lyst gene (PMID: 16518687, 22762706, 10594238, 10690356). CRISPR-generated *LYST*-deficient NK cells recapitulate a cellular phenotype that is consistent with that seen in humans (PMID: 29241728). In summary, *LYST* is definitively associated with Autosomal Recessive Chediak-Higahsi syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on May 29, 2020 (SOP Version 7). Due to the overlapping phenotype of Chediak-Higashi Syndrome (CHS) with immunodeficiency and immune dysregulation, the PIRD GCEP has provided an addendum to this gene curation: A large proportion of CHS patients (~85-90%) develop hyperinflammatory (or immune dysregulation) manifestations categorized ashemophagocytic lymphohistiocytosis. There are a subset of patients who develop attenuated disease, which is regarded as atypical CHS. *LYST* is a 429 kDa protein with several distinct domains involved in several aspects of vesicle trafficking. Patients with CHS have giant lysosomes or lysosome-related organelles in many cell subsets. NK cells in CHS patients have aberrant morphology and function, including lytic granule polarization and size among other features that severely compromise NK cell cytotoxicity. However, cytokine secretion in NK cells does not appear to be affected. Therefore, *LYST* appears to be important for regulated exocytosis but not for constitutive exocytosis, which supports the development of IFN-gamma-driven hyperinflammatory syndromes in CHS patients, in response to a trigger or stimulus (e.g. viral infection). In mouse models, it has been shown that Lyst regulates TLR3 and TLR4-mediated proinflammatory responses with increased susceptibility to bacterial infections. In patients with hypomorphic *LYST* variants, the attenuated disease is associated with subclinical or no immunodeficiency but rather a progressive, neurodegenerative phenotype in early adulthood. (PMIDs: 26478006; 27881733; https://doi.org/10.1186/1750-1172-8-46)
Inheritance Pattern: AR
Disease ID:MONDO:0008963
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0018133
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0008963
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0008963
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0008963
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0008963
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Dermatologic; Hematologic; Neurologic; Oncologic
Intervention: Allergy/Immunology/Infectious; Hematologic; Oncologic
Rationale: Individuals can have infection susceptibility, and prophylaxis and early and aggressive treatment of infections can be beneficial; Surveillance for hematologic complications and malignancy is warranted; For the accelerated phase, chemoimmunotherapy then transition to continuation therapy can be beneficial; For bleeding, platelet transfusions and DDAVP may be beneficial to prevent and/or treat episodes; BMT/HSCT has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to LYST variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000081.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 18 | 1171 | 6 | 1195 | ||
| missense | 1 | 9 | 1635 | 92 | 8 | 1745 |
| nonsense | 66 | 45 | 9 | 120 | ||
| start loss | 0 | |||||
| frameshift | 69 | 50 | 13 | 132 | ||
| splice donor/acceptor (+/-2bp) | 4 | 41 | 6 | 51 | ||
| Total | 140 | 145 | 1681 | 1263 | 14 | 3243 |
Highest pathogenic variant AF is 0.000026757334
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000072.2 | 51 | MANE Select | |
| Ensembl | ENSP00000374443.2 | 51 | MANE Select | |
| RefSeq | NP_001288294.1 | 51 | Standard | |
| Ensembl | ENSP00000513165.1 | 16 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| lyst | Danio rerio | Structure: liver Quality: fatty abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- lysosome organization
- protein transport
- leukocyte chemotaxis
- melanosome organization
- endosome to lysosome transport via multivesicular body sorting pathway
Molecular Function
- protein binding
Cellular Component
- cytoplasm
- microtubule cytoskeleton
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000389794
- Coding exons
- 51
- Length
- 222600
- Individuals with no LoFs
- 125658
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 90
- Defined
- 125748
- p
- 0.000358
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.41 | 1758 | 1.93e+3 | 0.910 | 0.000101 | 25039 |
| Missense (PolyPhen) | 592 | 754.77 | 0.78434 | 9855 | ||
| Synonymous | -0.232 | 706 | 698 | 1.01 | 0.0000375 | 7172 |
| Loss of Function | 9.58 | 44 | 184 | 0.239 | 0.0000104 | 2282 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00068 | 0.00062 | rare |
| Latino/Admixed American | 0.00032 | 0.00032 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0.00056 | 0.00055 | rare |
| European (Non-Finnish) | 0.00034 | 0.00033 | rare |
| South Asian | 0.00029 | 0.00029 | rare |
| Other | 0.00065 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May be required for sorting endosomal resident proteins into late multivesicular endosomes by a mechanism involving microtubules.;
Intolerance Scores
- LoFtool
- 0.601
- RVIS EVS
- -3.04
- RVIS percentile EVS
- 0.5
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.498
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |