LMAN1
protein-codinglectin, mannose binding 1
Gene summary
The protein encoded by this gene is a membrane mannose-specific lectin that cycles between the endoplasmic reticulum, endoplasmic reticulum-Golgi intermediate compartment, and cis-Golgi, functioning as a cargo receptor for glycoprotein transport. The protein has an N-terminal signal sequence, a calcium-dependent and pH-sensitive carbohydrate recognition domain, a stalk region that functions in oligomerization, a transmembrane domain, and a short cytoplasmic domain required for organelle targeting. Allelic variants of this gene are associated with the autosomal recessive disorder combined factor V-factor VIII deficiency. [provided by RefSeq, Jul 2015]
- F5F8D
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~31.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009206
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0009206
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0018175
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009206
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009206
Submitter: ClinGen
LMAN1 was first reported in relation to autosomal recessive factor V and factor VIII, combined deficiency in 1998 (Nichols WC, et al., 1998, PMID: 9546392). At least 38 unique variants (mostly nonsense and frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 15 probands in 3 publications (PMIDs: 9546392, 15876275, 9546392). Variants in this gene segregated with disease in 3 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism or disease is homozygous loss of function. This gene disease association is supported by its biochemical function as a cargo receptor for the ER-to-Golgi transport of factor V and factor VIII (PMID: 10551804), its interaction with MCFD2 (PMID: 15886209) which is also implicated in this disease, and a knockout mouse model (PMID: 21795745) that also exhibits reductions of both factor V and factor VIII. In summary, LMAN1 is definitively associated with autosomal recessive inheritance of factor V and factor VIII, combined deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Clinical Genomic Database (CGD)
Manifestation: Hematologic
Intervention: Hematologic
Rationale: Individuals can suffer from bleeding diatheses of varying severity, and preventive measures related to bleeding episodes can be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to LMAN1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005570.4. 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 | 1 | 4 | 7 | 1 | 13 | |
| missense | 96 | 10 | 106 | |||
| nonsense | 3 | 1 | 4 | |||
| start loss | 1 | 1 | ||||
| frameshift | 4 | 2 | 1 | 7 | ||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 1 | 3 | ||
| Total | 9 | 5 | 102 | 17 | 1 | 134 |
Highest pathogenic variant AF is 0.000035481655
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005561.1 | 13 | MANE Select | |
| Ensembl | ENSP00000251047.4 | 13 | MANE Select | |
| Ensembl | ENSP00000574766.1 | 13 | Standard | |
| Ensembl | ENSP00000574766.1 | 13 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Protein processing in endoplasmic reticulum - Homo sapiens (human)
- Dengue-2 Interactions with Complement and Coagulation Cascades
- Complement and Coagulation Cascades
- Vesicle-mediated transport
- Membrane Trafficking
Biological Process
- protein folding
- endoplasmic reticulum to Golgi vesicle-mediated transport
- endoplasmic reticulum organization
- Golgi organization
- blood coagulation
Molecular Function
- protein binding
- mannose binding
- metal ion binding
- unfolded protein binding
Cellular Component
- Golgi membrane
- endoplasmic reticulum membrane
- endoplasmic reticulum-Golgi intermediate compartment
- cytosol
- ER to Golgi transport vesicle membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000251047
- Coding exons
- 13
- Length
- 32140
- Individuals with no LoFs
- 125702
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 46
- Defined
- 125748
- p
- 0.000183
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0627 | 270 | 273 | 0.989 | 0.0000139 | 3357 |
| Missense (PolyPhen) | 78 | 90.325 | 0.86355 | 1152 | ||
| Synonymous | -0.381 | 101 | 96.2 | 1.05 | 0.00000493 | 947 |
| Loss of Function | 3.50 | 10 | 31.1 | 0.322 | 0.00000178 | 345 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00018 | rare |
| Latino/Admixed American | 0.00038 | 0.00038 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00055 | 0.00054 | rare |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00012 | 0.00011 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Mannose-specific lectin. May recognize sugar residues of glycoproteins, glycolipids, or glycosylphosphatidyl inositol anchors and may be involved in the sorting or recycling of proteins, lipids, or both. The LMAN1-MCFD2 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins. {ECO:0000269|PubMed:12717434, ECO:0000269|PubMed:13130098}.;
- Disease
- DISEASE: Factor V and factor VIII combined deficiency 1 (F5F8D1) [MIM:227300]: A blood coagulation disorder characterized by bleeding symptoms similar to those in hemophilia or parahemophilia, that are caused by single deficiency of FV or FVIII, respectively. The most common symptoms are epistaxis, menorrhagia, and excessive bleeding during or after trauma. Plasma levels of coagulation factors V and VIII are in the range of 5 to 30% of normal. {ECO:0000269|PubMed:10090935, ECO:0000269|PubMed:19787799}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.175
Intolerance Scores
- LoFtool
- 0.443
- RVIS EVS
- -0.05
- RVIS percentile EVS
- 50.34
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.641
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |