MCOLN1

mucolipin TRP cation channel 1, the group of Transient receptor potential cation channels

Basic information

Region (hg38): 19:7522623-7534009

Links

ENSG00000090674 ∙ NCBI:57192 ∙ OMIM:605248 ∙ HGNC:13356 ∙ Uniprot:Q9GZU1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• mucolipidosis type IV (Definitive), mode of inheritance: AR
• mucolipidosis type IV (Definitive), mode of inheritance: AR
• mucolipidosis type IV (Strong), mode of inheritance: AR
• mucolipidosis type IV (Definitive), mode of inheritance: AR
• mucolipidosis type IV (Strong), mode of inheritance: AR
• mucolipidosis type IV (Supportive), mode of inheritance: AR
• mucolipidosis type IV (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Mucolipidosis IV	AR	General	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	Biochemical; Neurologic; Ophthalmologic	4365943; 166049; 7114093; 3918453; 2438637; 1789285; 9323557; 9600972; 9710036; 10973263; 11030752; 15523648; 17239335; 19006653; 20159435

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MCOLN1 gene.

• Mucolipidosis type IV (638 variants)
• not provided (76 variants)
• Inborn genetic diseases (60 variants)
• not specified (9 variants)
• Mucolipidosis (1 variants)
• Abnormality of the nervous system (1 variants)
• Hereditary spastic paraplegia 39 (1 variants)
• Spastic Paraplegia, Recessive (1 variants)
• Hereditary spastic paraplegia 5A (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MCOLN1 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			2	260		262
missense		5	103	5	1	114
nonsense	17	8	1			26
start loss						0
frameshift	23	17	3			43
inframe indel		1	2			3
splice donor/acceptor (+/-2bp)	3	18		1		22
splice region			11	51	1	63
non coding			12	86	21	119
Total	43	49	123	352	22

Highest pathogenic variant AF is 0.0000788

Variants in MCOLN1

This is a list of pathogenic ClinVar variants found in the MCOLN1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
19-7522649-T-G		Mucolipidosis type IV	Uncertain significance (Jan 13, 2018)
19-7522663-G-T		Mucolipidosis type IV	Uncertain significance (Jan 13, 2018)
19-7522664-A-T		Mucolipidosis type IV	Uncertain significance (Jan 12, 2018)
19-7522756-A-G		Mucolipidosis type IV	Likely benign (Dec 02, 2023)
19-7522757-G-GC		Mucolipidosis type IV	Likely pathogenic (May 18, 2022)
19-7522759-C-T		Mucolipidosis type IV	Likely benign (Nov 04, 2023)
19-7522761-C-A		Inborn genetic diseases	Uncertain significance (Feb 10, 2023)
19-7522765-G-C		Mucolipidosis type IV	Likely benign (Feb 16, 2023)
19-7522766-G-T		Mucolipidosis type IV	Conflicting classifications of pathogenicity (Jan 31, 2024)
19-7522767-G-T			Uncertain significance (Jul 22, 2019)
19-7522768-T-G		Mucolipidosis type IV	Likely benign (Sep 18, 2021)
19-7522771-G-T		Mucolipidosis type IV	Likely benign (Jan 22, 2022)
19-7522774-C-A		Mucolipidosis type IV	Likely benign (Dec 12, 2023)
19-7522774-C-T		Mucolipidosis type IV • Inborn genetic diseases	Conflicting classifications of pathogenicity (Jan 28, 2024)
19-7522779-C-T		Inborn genetic diseases	Uncertain significance (Aug 22, 2023)
19-7522782-G-A		Mucolipidosis type IV	Likely pathogenic (Jan 31, 2024)
19-7522783-T-TGAG		Mucolipidosis type IV	Likely benign (Dec 07, 2020)
19-7522790-G-A		Mucolipidosis type IV	Likely benign (Nov 03, 2021)
19-7522791-C-T		Mucolipidosis type IV	Likely benign (Dec 28, 2021)
19-7522794-G-A		Mucolipidosis type IV	Likely benign (Dec 19, 2023)
19-7522793-G-GGCGGCACCGTGGGGCCCCGA		Mucolipidosis type IV	Likely benign (Jul 17, 2023)
19-7522795-C-T		Mucolipidosis type IV	Likely benign (Jul 28, 2023)
19-7522800-C-T		Mucolipidosis type IV	Likely benign (Jan 05, 2023)
19-7522801-C-T		Mucolipidosis type IV	Likely benign (Mar 08, 2023)
19-7522910-G-A			Likely benign (Oct 21, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MCOLN1	protein_coding	protein_coding	ENST00000264079	14	11384

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000580	0.999	125655	0	93	125748	0.000370

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.61	272	358	0.760	0.0000264	3769
Missense in Polyphen		98	150.43	0.65147		1738
Synonymous	-1.52	187	162	1.15	0.0000129	1199
Loss of Function	3.23	11	30.1	0.365	0.00000176	318

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000235	0.000235
Ashkenazi Jewish	0.00427	0.00428
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.000318	0.000316
Middle Eastern	0.0000544	0.0000544
South Asian	0.000196	0.000196
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Nonselective cation channel probably playing a role in the regulation of membrane trafficking events and of metal homeostasis. Proposed to play a major role in Ca(2+) release from late endosome and lysosome vesicles to the cytoplasm, which is important for many lysosome-dependent cellular events, including the fusion and trafficking of these organelles, exocytosis and autophagy (PubMed:11013137, PubMed:12459486, PubMed:15336987, PubMed:14749347, PubMed:29019983). Required for efficient uptake of large particles in macrophages in which Ca(2+) release from the lysosomes triggers lysosomal exocytosis. May also play a role in phagosome-lysosome fusion (By similarity). Involved in lactosylceramide trafficking indicative for a role in the regulation of late endocytic membrane fusion/fission events (PubMed:16978393). By mediating lysosomal Ca(2+) release is involved in regulation of mTORC1 signaling and in mTOR/TFEB- dependent lysosomal adaptation to environmental cues such as nutrient levels (PubMed:27787197, PubMed:25733853). Seems to act as lysosomal active oxygen species (ROS) sensor involved in ROS- induced TFEB activation and autophagy (PubMed:27357649). Functions as a Fe(2+) permeable channel in late endosomes and lysosomes (PubMed:18794901). Proposed to play a role in zinc homeostasis probably implicating its association with TMEM163 (PubMed:25130899) In adaptive immunity, TRPML2 and TRPML1 may play redundant roles in the function of the specialized lysosomes of B cells (By similarity). {ECO:0000250|UniProtKB:Q99J21, ECO:0000269|PubMed:12459486, ECO:0000269|PubMed:14749347, ECO:0000269|PubMed:15336987, ECO:0000269|PubMed:16978393, ECO:0000269|PubMed:18794901, ECO:0000269|PubMed:25130899, ECO:0000269|PubMed:25733853, ECO:0000269|PubMed:27357649, ECO:0000269|PubMed:27787197, ECO:0000269|PubMed:29019983, ECO:0000305|PubMed:11013137}.
• Disease: DISEASE: Mucolipidosis 4 (ML4) [MIM:252650]: An autosomal recessive lysosomal storage disorder characterized by severe psychomotor retardation and ophthalmologic abnormalities, including corneal opacity, retinal degeneration and strabismus. Storage bodies of lipids and water-soluble substances are seen by electron microscopy in almost every cell type of the patients. Most patients are unable to speak or walk independently and reach a maximal developmental level of 1-2 years. All patients have constitutive achlorhydia associated with a secondary elevation of serum gastrin levels. {ECO:0000269|PubMed:10973263, ECO:0000269|PubMed:11013137, ECO:0000269|PubMed:11030752, ECO:0000269|PubMed:11317355, ECO:0000269|PubMed:12182165, ECO:0000269|PubMed:14749347, ECO:0000269|PubMed:15178326, ECO:0000269|PubMed:15523648, ECO:0000269|PubMed:16978393, ECO:0000269|PubMed:18794901, ECO:0000269|PubMed:21256127, ECO:0000269|PubMed:28112729}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Lysosome - Homo sapiens (human);Iron metabolism in placenta;Transferrin endocytosis and recycling;Stimuli-sensing channels;Ion channel transport;Transport of small molecules;TRP channels;Iron uptake and transport (Consensus)

Recessive Scores

• pRec: 0.172

Intolerance Scores

• loftool: 0.270
• rvis_EVS: -0.93
• rvis_percentile_EVS: 9.61

Haploinsufficiency Scores

• pHI: 0.239
• hipred: Y
• hipred_score: 0.563
• ghis: 0.531

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.957

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Mcoln1
• 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); hematopoietic system phenotype; 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; renal/urinary system 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); digestive/alimentary phenotype; vision/eye 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); growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); homeostasis/metabolism phenotype; muscle phenotype

Zebrafish Information Network

• Gene name: mcoln1a
• Affected structure: cornea
• Phenotype tag: abnormal
• Phenotype quality: increased amount

Gene ontology

• Biological process: adaptive immune response;cation transport;calcium-mediated signaling;transferrin transport;iron ion transmembrane transport;release of sequestered calcium ion into cytosol;protein homotetramerization;calcium ion transmembrane transport;cellular response to calcium ion;cellular response to pH;autophagosome maturation
• Cellular component: phagocytic cup;lysosome;lysosomal membrane;late endosome;cytosol;plasma membrane;integral component of plasma membrane;endosome membrane;integral component of membrane;phagocytic vesicle membrane;late endosome membrane;cell projection;receptor complex
• Molecular function: cation channel activity;calcium channel activity;iron ion transmembrane transporter activity;protein binding;lipid binding;NAADP-sensitive calcium-release channel activity;intracellular phosphatidylinositol-3,5-bisphosphate-sensitive cation channel activity;ligand-gated calcium channel activity