EXT1

Chr 8ADSomatic

exostosin glycosyltransferase 1

Also known as: EXT, LGCR, LGS, TRPS2, TTV

NCBI Gene: 2131 ENSG00000182197 UniProt: Q16394 OMIM: 133700

This gene encodes an endoplasmic reticulum glycosyltransferase that catalyzes heparan sulfate chain elongation during biosynthesis. Loss-of-function mutations cause multiple exostoses type 1, an autosomal dominant disorder characterized by benign bone tumors that can undergo malignant transformation to chondrosarcoma. The pathogenic mechanism involves haploinsufficiency leading to disrupted heparan sulfate production and abnormal bone growth regulation.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes an endoplasmic reticulum-resident type II transmembrane glycosyltransferase involved in the chain elongation step of heparan sulfate biosynthesis. Mutations in this gene cause the type I form of multiple exostoses. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/SomaticLOEUF 0.263 OMIM phenotypes

Clinical Summary— EXT1

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Gene-Disease Validity (ClinGen)

exostoses, multiple, type 1 · ADDefinitive

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 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

552 unique Pathogenic / Likely Pathogenic· 394 VUS of 1269 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — EXT1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.26LOEUF

pLI 0.997

Z-score 4.86

OE 0.11 (0.06–0.26)

Highly constrained

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

Missense Constraint?

1.67Z-score

OE missense 0.77 (0.70–0.84)

317 obs / 412.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.11 (0.06–0.26)

0≤0.351.4

Missense OE?0.77 (0.70–0.84)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 4 / 35.0Missense obs/exp: 317 / 412.2Syn Z: -0.73

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveEXT1-related multiple exostosesLOFAD

definitiveEXT1-related trichorhinopharangeal syndrome (Langer-Giedon)LOFAD

This gene — mechanism propensity

0.3793th %ile

GOF

0.3292th %ile

LOF

0.67top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 85% of P/LP variants are LoF · LOEUF 0.26 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFLanger-Giedion's syndrome (LGS) or trichorhinophalangeal syndrome type II (TRPS II; MIM:150230) is a contiguous gene deletion syndrome caused by the haploinsufficiency of the TRPS1 and EXT1 genes.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 31976145 ↗

ClinVar Variant Classifications

1269 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic476

Likely Pathogenic76

VUS394

Likely Benign223

Benign46

Conflicting38

476

Pathogenic

Likely Pathogenic

394

VUS

223

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	423	27	26	0	476
Likely Pathogenic	44	28	4	0	76
VUS	9	347	35	3	394
Likely Benign	0	9	73	141	223
Benign	0	5	29	12	46
Conflicting	—				38
Total	476	416	167	156	1,253

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

View in ClinVar →

65 pathogenic / likely-pathogenic (of 73) ClinVar copy-number / structural variants overlap EXT1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →