CHSY1

Chr 15AR

chondroitin sulfate synthase 1

Also known as: CHSY, CSS1, ChSy-1, TPBS

NCBI Gene: 22856 ENSG00000131873 UniProt: Q86X52 OMIM: 608183

This protein functions as a dual transferase enzyme that synthesizes chondroitin sulfate by adding both glucuronic acid and N-acetylgalactosamine to the growing polymer chain, and negatively regulates bone formation through modulation of NOTCH signaling. Mutations cause Temtamy preaxial brachydactyly syndrome, which involves limb malformations, inherited in an autosomal recessive pattern. The gene shows high constraint against loss-of-function variants (LOEUF 0.405), indicating that such mutations are typically not tolerated.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the chondroitin N-acetylgalactosaminyltransferase family. These enzymes possess dual glucuronyltransferase and galactosaminyltransferase activity and play critical roles in the biosynthesis of chondroitin sulfate, a glycosaminoglycan involved in many biological processes including cell proliferation and morphogenesis. Decreased expression of this gene may play a role in colorectal cancer, and mutations in this gene are a cause of temtamy preaxial brachydactyly syndrome. [provided by RefSeq, Dec 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.411 OMIM phenotype

Clinical Summary— CHSY1

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Gene-Disease Validity (ClinGen)

temtamy preaxial brachydactyly syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.71) — some intolerance to loss-of-function variants.

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 186 VUS of 326 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.708

Z-score 3.81

OE 0.19 (0.10–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.83Z-score

OE missense 0.89 (0.81–0.96)

376 obs / 424.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.19 (0.10–0.41)

0≤0.351.4

Missense OE?0.89 (0.81–0.96)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 5 / 26.0Missense obs/exp: 376 / 424.1Syn Z: -1.96

ClinVar Variant Classifications

326 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic1

VUS186

Likely Benign86

Benign36

Conflicting6

Pathogenic

Likely Pathogenic

186

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	2	1	0	8
Likely Pathogenic	1	0	0	0	1
VUS	0	181	3	2	186
Likely Benign	0	6	12	68	86
Benign	0	4	18	14	36
Conflicting	—				6
Total	6	193	34	84	323

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

View in ClinVar →

80 pathogenic / likely-pathogenic (of 100) ClinVar copy-number / structural variants overlap CHSY1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →