LARGE1

LARGE xylosyl- and glucuronyltransferase 1, the group of Glycosyltransferase family 8|MicroRNA protein coding host genes

Basic information

Region (hg38): 22:33162226-33922841

Previous symbols: [ "LARGE" ]

Links

ENSG00000133424 ∙ NCBI:9215 ∙ OMIM:603590 ∙ HGNC:6511 ∙ Uniprot:O95461 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (Strong), mode of inheritance: AR
• muscular dystrophy-dystroglycanopathy, type A (Supportive), mode of inheritance: AR
• congenital muscular dystrophy with intellectual disability (Supportive), mode of inheritance: AR
• muscular dystrophy-dystroglycanopathy type B6 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 6; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 6	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	Musculoskeletal; Neurologic; Ophthalmologic	12966029; 17878207; 17436019; 19067344; 19299310; 21248746

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the LARGE1 gene.

• Muscular_dystrophy-dystroglycanopathy_type_B6 (773 variants)
• not_provided (206 variants)
• Muscular_dystrophy-dystroglycanopathy_(congenital_with_brain_and_eye_anomalies),_type_A6 (64 variants)
• not_specified (58 variants)
• LARGE1-related_disorder (30 variants)
• Inborn_genetic_diseases (12 variants)
• Muscular_dystrophy-dystroglycanopathy_(congenital_with_brain_and_eye_anomalies),_type_A1 (3 variants)
• Muscular_dystrophy (2 variants)
• LARGE1-Related_Disorders (1 variants)
• Retinitis_pigmentosa (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LARGE1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000133642.5. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	301	6	308
missense	4	2	265	11		282
nonsense	8	2	1			11
start loss						0
frameshift	15	2				17
splice donor/acceptor (+/-2bp)		7	1			8
Total	27	13	268	312	6

Highest pathogenic variant AF is 0.0000129969

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LARGE1	protein_coding	protein_coding	ENST00000354992	14	760618

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.989	0.0107	125730	0	18	125748	0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.99	347	468	0.741	0.0000322	4978
Missense in Polyphen		121	210.99	0.5735		2290
Synonymous	-1.29	215	192	1.12	0.0000135	1469
Loss of Function	4.99	6	40.1	0.150	0.00000210	424

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000868	0.0000868
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.0000969	0.0000967
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000653	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Bifunctional glycosyltransferase with both xylosyltransferase and beta-1,3-glucuronyltransferase activities involved in the biosynthesis of the phosphorylated O-mannosyl trisaccharide (N-acetylgalactosamine-beta-3-N-acetylglucosamine- beta-4-(phosphate-6-)mannose), a carbohydrate structure present in alpha-dystroglycan (DAG1) (PubMed:22223806). Phosphorylated O- mannosyl trisaccharid is required for binding laminin G-like domain-containing extracellular proteins with high affinity and plays a key role in skeletal muscle function and regeneration. LARGE elongates the glucuronyl-beta-1,4-xylose-beta disaccharide primer structure initiated by B3GNT1/B4GAT1 by adding repeating units [-3-Xylose-alpha-1,3-GlcA-beta-1-] to produce a heteropolysaccharide (PubMed:25279699). {ECO:0000269|PubMed:15661757, ECO:0000269|PubMed:15752776, ECO:0000269|PubMed:21987822, ECO:0000269|PubMed:22223806, ECO:0000269|PubMed:25138275, ECO:0000269|PubMed:25279697, ECO:0000269|PubMed:25279699}.
• Disease: DISEASE: Muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies A6 (MDDGA6) [MIM:613154]: An autosomal recessive disorder characterized by congenital muscular dystrophy associated with cobblestone lissencephaly and other brain anomalies, eye malformations, profound mental retardation, and death usually in the first years of life. Included diseases are the more severe Walker-Warburg syndrome and the slightly less severe muscle-eye-brain disease. {ECO:0000269|PubMed:19067344, ECO:0000269|PubMed:19299310, ECO:0000269|PubMed:24709677}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Mannose type O-glycan biosynthesis - Homo sapiens (human);Post-translational protein modification;Metabolism of proteins;O-linked glycosylation (Consensus)

Recessive Scores

• pRec: 0.349

Intolerance Scores

• rvis_EVS: -0.62
• rvis_percentile_EVS: 17.45

Haploinsufficiency Scores

• pHI: 0.0807
• hipred: Y
• hipred_score: 0.641
• ghis: 0.614

Essentials

• essential_gene_gene_trap: N

Mouse Genome Informatics

• Gene name: Large1
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); reproductive system 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); 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); 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); hearing/vestibular/ear phenotype; digestive/alimentary phenotype; vision/eye phenotype; immune system phenotype; skeleton phenotype; growth/size/body region phenotype; muscle phenotype; craniofacial phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: N-acetylglucosamine metabolic process;protein glycosylation;protein O-linked glycosylation;glycosphingolipid biosynthetic process;glycoprotein biosynthetic process;protein O-linked mannosylation;skeletal muscle tissue regeneration;muscle cell cellular homeostasis;skeletal muscle organ development
• Cellular component: Golgi membrane;Golgi apparatus;integral component of Golgi membrane
• Molecular function: acetylglucosaminyltransferase activity;glucuronosyltransferase activity;transferase activity, transferring glycosyl groups;manganese ion binding;UDP-xylosyltransferase activity;xylosyltransferase activity