EML1
protein-codingEMAP like 1, the group of EMAP like|WD repeat domain containing
Gene summary
Human echinoderm microtubule-associated protein-like is a strong candidate for the Usher syndrome type 1A gene. Usher syndromes (USHs) are a group of genetic disorders consisting of congenital deafness, retinitis pigmentosa, and vestibular dysfunction of variable onset and severity depending on the genetic type. The disease process in USHs involves the entire brain and is not limited to the posterior fossa or auditory and visual systems. The USHs are catagorized as type I (USH1A, USH1B, USH1C, USH1D, USH1E and USH1F), type II (USH2A and USH2B) and type III (USH3). The type I is the most severe form. Gene loci responsible for these three types are all mapped. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
- EMAPL
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~204.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0010873
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0010873
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0010873
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0020491
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0010873
Submitter: ClinGen
*EML1* was first reported in relation to autosomal recessive *EML1*-related ribbon-like subcortical heterotopia in 2014 (Kielar et al., PMID: 24859200). *EML1*-related ribbon-like subcortical heterotopia is characterized by ribbon-like subcortical heterotopia, and may also include polymicrogyria, hydrocephalus, developmental delay, and intellectual disability. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in inheritance pattern or phenotypic variability between band heterotopia (MIM:600348) and hydrocephalus (no MIM). Therefore, the following disease entities have been lumped into one disease entity, *EML1*-related ribbon-like subcortical heterotopia. Four missense, two nonsense, and one large deletion variants that have been reported in six probands in four publications (PMIDs: 24859200, 28556411, 31710781, 34211111) are included in this curation. The mechanism of pathogenicity is unknown at this time. This gene-disease relationship is also supported by expression studies, a mouse model, rescue studies, protein-protein interactions, and functional alteration in patient cells (PMIDs: 24859200, 31390572, 34211111). In summary, there is definitive evidence supporting the relationship between *EML1* and autosomal recessive *EML1*-related ribbon-like subcortical heterotopia. 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 Brain Malformations GCEP on the meeting date May 27th, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0010873
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to EML1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004434.3. 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 | 2 | 66 | 1 | 69 | ||
| missense | 1 | 1 | 101 | 4 | 1 | 108 |
| nonsense | 2 | 2 | 1 | 5 | ||
| start loss | 0 | |||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | 4 | |||
| Total | 7 | 3 | 106 | 70 | 2 | 188 |
Highest pathogenic variant AF is 0.0000013692703
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004425.2 | 22 | MANE Select | |
| Ensembl | ENSP00000262233.7 | 22 | MANE Select | |
| RefSeq | NP_001008707.1 | 23 | Standard | |
| RefSeq | NP_001362340.1 | 22 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| eml1 | Danio rerio | Structure: retinal cone cell Quality: photosensitive abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- microtubule cytoskeleton organization
- hematopoietic progenitor cell differentiation
- mitotic spindle organization
- neuroblast proliferation
- brain development
Molecular Function
- calcium ion binding
- protein binding
- microtubule binding
- tubulin binding
Cellular Component
- cytosol
- microtubule
- microtubule associated complex
- microtubule cytoskeleton
- perinuclear region of cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000334192
- Coding exons
- 23
- Length
- 204368
- Individuals with no LoFs
- 125718
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 30
- Defined
- 125748
- p
- 0.000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.45 | 326 | 477 | 0.684 | 0.0000278 | 5435 |
| Missense (PolyPhen) | 108 | 197.28 | 0.54744 | 2169 | ||
| Synonymous | 0.736 | 176 | 189 | 0.932 | 0.0000126 | 1639 |
| Loss of Function | 5.63 | 8 | 51.6 | 0.155 | 0.00000289 | 571 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0012 | 0.0012 | notable |
| Latino/Admixed American | 0.000030 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000062 | 0.000062 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Modulates the assembly and organization of the microtubule cytoskeleton, and probably plays a role in regulating the orientation of the mitotic spindle and the orientation of the plane of cell division. Required for normal proliferation of neuronal progenitor cells in the developing brain and for normal brain development. Does not affect neuron migration per se. {ECO:0000250|UniProtKB:Q05BC3}.;
- Disease
- DISEASE: Band heterotopia (BH) [MIM:600348]: A brain malformation of the lissencephaly spectrum, resulting from disordered neuronal migration and characterized by bands of gray matter interposed in the central white matter. Disease features include severe developmental delay with intellectual disability, enlarged head circumference, periventricular and ribbon-like subcortical heterotopia, polymicrogyria and agenesis of the corpus callosum. {ECO:0000269|PubMed:24859200}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.164
Intolerance Scores
- LoFtool
- 0.419
- RVIS EVS
- -0.42
- RVIS percentile EVS
- 25.73
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.564
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |