LARGE1

Chr 22AR

LARGE xylosyl- and glucuronyltransferase 1

Also known as: LARGE, MDC1D, MDDGA6, MDDGB6

NCBI Gene: 9215 ENSG00000133424 UniProt: O95461 OMIM: 603590

LARGE1 encodes a glycosyltransferase that adds xylose and glucuronic acid to alpha-dystroglycan, enabling alpha-dystroglycan to bind laminin 211 and neurexin. Autosomal recessive mutations cause muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A6) or intellectual disability (type B6) due to abnormal glycosylation of alpha-dystroglycan. Loss-of-function mutations disrupt the critical glycosylation pathway required for proper dystroglycan function in muscle and brain development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the N-acetylglucosaminyltransferase gene family. It encodes a glycosyltransferase which participates in glycosylation of alpha-dystroglycan, and may carry out the synthesis of glycoprotein and glycosphingolipid sugar chains. It may also be involved in the addition of a repeated disaccharide unit. The protein encoded by this gene is the glycotransferase that adds the final xylose and glucuronic acid to alpha-dystroglycan and thereby allows alpha-dystroglycan to bind ligands including laminin 211 and neurexin. Mutations in this gene cause several forms of congenital muscular dystrophy characterized by cognitive disability and abnormal glycosylation of alpha-dystroglycan. Alternative splicing of this gene results in multiple transcript variants that encode the same protein. [provided by RefSeq, May 2018]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.292 OMIM phenotypes

Clinical Summary— LARGE1

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Gene-Disease Validity (ClinGen)

muscular dystrophy-dystroglycanopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

70 unique Pathogenic / Likely Pathogenic· 333 VUS of 1050 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.29LOEUF

pLI 0.989

Z-score 4.99

OE 0.15 (0.08–0.29)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.99Z-score

OE missense 0.74 (0.68–0.81)

347 obs / 468.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.15 (0.08–0.29)

0≤0.351.4

Missense OE?0.74 (0.68–0.81)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 6 / 40.1Missense obs/exp: 347 / 468.3Syn Z: -1.29

ClinVar Variant Classifications

1050 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic56

Likely Pathogenic14

VUS333

Likely Benign529

Benign69

Conflicting36

Pathogenic

Likely Pathogenic

333

VUS

529

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	23	3	30	0	56
Likely Pathogenic	11	1	2	0	14
VUS	2	275	55	1	333
Likely Benign	0	6	232	291	529
Benign	0	0	61	8	69
Conflicting	—				36
Total	36	285	380	300	1,037

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

25 pathogenic / likely-pathogenic (of 62) ClinVar copy-number / structural variants overlap LARGE1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →