MLC1
protein-codingmodulator of VRAC current 1
Gene summary
The function of this gene product is unknown; however, homology to other proteins suggests that it may be an integral membrane transporter. Mutations in this gene have been associated with megalencephalic leukoencephalopathy with subcortical cysts, an autosomal recessive neurological disorder. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~26.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0024555
Submitter: Myriad Women's Health
Inheritance Pattern: AR
Disease ID:MONDO:0024555
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0024555
Submitter: ClinGen
*MLC1* was first reported in relation to autosomal recessive megalencephalic leukoencephalopathy with subcortical cysts 1 in 2001(Leegwater et al., PMID: 11254442). Prior to this in 2000, (Topçu et al., PMID: 10677334) the location of the gene was mapped to Chromosome 22qtel. Prior to the identification of the gene, the condition was first clinically described in 1995 (Van der Knaap et al., PMID: 7695231). A group of 8 children were described with infantile onset megaloencepahly and cerebral leukodystrophy with slowly progressive ataxia and spasticity. Brain MRI were significant for diffuse abnormality in signal intensity and swelling of the cerebral hemispheral white matter with cyst-like spaces in the frontoparietal and anterior-temporal subcortical areas. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms or inheritance pattern. Therefore, there is one disease entity, Megalencephalic leukoencephalopathy with subcortical cysts 1 (OMIM:604004). 11 variants (missense, nonsense, frameshift,) that have been reported in 9 probands in 5 publications (PMIDs: 25497041, 32056211, 12189496, 21145992, 27389245) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence (functional alteration, expression studies) (PMIDs: 18757878). Lower expression in rat astrocytes and altered pH distribution. In summary, there is definitive evidence supporting the relationship between *MLC1 *and autosomal recessive megalencephalic leukoencephalopathy with subcortical cysts 1. 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 Leukodystrophy and Leukoencephalopathy GCEP at the meeting November 25, 2024 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0024555
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0011391
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0024555
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0024555
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0024555
Submitter: Natera
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 MLC1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_015166.4. 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 | 9 | 178 | 187 | |||
| missense | 6 | 31 | 135 | 12 | 1 | 185 |
| nonsense | 4 | 17 | 1 | 22 | ||
| start loss | 1 | 1 | ||||
| frameshift | 33 | 23 | 2 | 58 | ||
| splice donor/acceptor (+/-2bp) | 7 | 31 | 2 | 40 | ||
| Total | 50 | 103 | 149 | 190 | 1 | 493 |
Highest pathogenic variant AF is 0.000054864486
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_055981.1 | 11 | MANE Select | |
| Ensembl | ENSP00000310375.6 | 11 | MANE Select | |
| RefSeq | NP_001363401.1 | 11 | Standard | |
| RefSeq | NP_001363402.1 | 11 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| mlc1 | Danio rerio | Structure: midbrain Quality: physical object quality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- erk and pi-3 kinase are necessary for collagen binding in corneal epithelia
- integrin signaling pathway
- mcalpain and friends in cell motility
Biological Process
- ion transport
- protein transport
- vesicle-mediated transport
- positive regulation of intracellular transport
- regulation of response to osmotic stress
Molecular Function
- protein binding
- protein transporter activity
- protein-containing complex binding
Cellular Component
- cytoplasm
- lysosome
- endosome
- early endosome
- endoplasmic reticulum
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000311597
- Coding exons
- 11
- Length
- 26512
- Individuals with no LoFs
- 125705
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 42
- Defined
- 125748
- p
- 0.000171
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.203 | 210 | 218 | 0.961 | 0.0000150 | 2409 |
| Missense (PolyPhen) | 114 | 110.19 | 1.0346 | 1273 | ||
| Synonymous | 0.415 | 96 | 101 | 0.948 | 0.00000820 | 785 |
| Loss of Function | 1.03 | 14 | 18.8 | 0.744 | 0.00000104 | 214 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00026 | 0.00025 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.00019 | 0.00018 | rare |
| South Asian | 0.00033 | 0.00033 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Regulates the response of astrocytes to hypo-osmosis by promoting calcium influx. {ECO:0000269|PubMed:22328087}.;
Recessive Scores
- pRec
- 0.206
Intolerance Scores
- LoFtool
- 0.0931
- RVIS EVS
- 0
- RVIS percentile EVS
- 53.85
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.793
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |