HYAL1

protein-coding

hyaluronidase 1, the group of Hyaluronidases

Gene summary

This gene encodes a lysosomal hyaluronidase. Hyaluronidases intracellularly degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix. Hyaluronan is thought to be involved in cell proliferation, migration and differentiation. This enzyme is active at an acidic pH and is the major hyaluronidase in plasma. Mutations in this gene are associated with mucopolysaccharidosis type IX, or hyaluronidase deficiency. The gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_033159.4

Inheritance

ClinVar variants

P:54U:152B:192

Top phenotype

Mucopolysaccharidosis type IX

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr3:50,299,890-50,312,381

External References & Databases

Ensembl (ENSG00000114378)

Transcript & Mutation Effects

hg38 • Region Span ~12.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mucopolysaccharidosis type 9MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011093

Submitter: ClinGen

The relationship between HYAL1 and Mucopolysaccharidosis IX (MPS IX), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of November, 2022. HYAL1 encodes a lysosomal enzyme, hyaluronidase 1, which breaks down hyaluronic acid or hyaluronan (HA), one of the major glycosaminoglycans of the extracellular matrix, especially of soft connective tissue. MPS IX or hyaluronidase deficiency is characterized by short stature, dysmoprhic features, periarticular masses, generalized swelling and elevated serum HA. MPS IX may also present similar to juvenile idiopathic arthritis. HYAL1 was first reported in relation to autosomal recessive MPS IX in 1999 (Triggs-Raine et al, PMID: 10339581). Variants reported in this gene are mostly putative loss of function variants, all of them being nonsense and frameshift variants. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (4.6 points): There have only been 2 published patients (and two siblings of one of the probands, PMID: 21559944) from 3 publications, till date, reported with biallelic variants in HYAL1 (PMID: 8793927, 10339581, 21559944). The mechanism of disease is loss of function. Summary of experimental data (2.5 points): This gene-disease association is supported by expression assays and an animal model. HYAL1 is highly expressed in the liver, which is the site of hyaluronidase degradation. It is absent in the brain, which correlates with the absence of neurological features in patients with MPS IX (PMID: 10339581). The HYAL1 knock-out mouse model shows absence of hyaluronidase activity, pericellular accumulation of HA and bony outgrowth development, consistent with osteoarthritis (PMID: 18344557) and reduced bone mineral density (PMID: 35710820). In summary, the level of evidence to support the gene-disease relationship of HYAL1 an autosomal recessive MPS IX is moderate. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was first approved by the ClinGen Lysosomal Diseases GCEP on Dec 6 2022 and was re-evaluted, with no changes, on Sept 12, 2025 (SOP v11).

mucopolysaccharidosis type 9LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0011093

Submitter: Ambry Genetics

mucopolysaccharidosis type 9SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011093

Submitter: Orphanet

mucopolysaccharidosis type 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011093

Submitter: Labcorp Genetics (formerly Invitae)

mucopolysaccharidosis type 9DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011093

Submitter: G2P

mucopolysaccharidosis type 9MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011093

Submitter: PanelApp Australia

mucopolysaccharidosis type 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011093

Submitter: Genomics England PanelApp

mucopolysaccharidosis type 9MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011093

Submitter: Natera

Clinical Genomic Database (CGD)

Mucopolysaccharidosis type IXAR

Manifestation: Biochemical; Craniofacial; Dermatologic; Musculoskeletal

Intervention: General

Rationale: 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

Refs: 8793927; 10339581

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HYAL1 variants in ClinVar

4 Conditions Cataloged

Deficiency of hyaluronoglucosaminidaseTotal: 376

not specifiedTotal: 75

HYAL1-related disorderTotal: 17

not providedTotal: 16

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_033159.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	177 clinvar	1 clinvar	184
missense			140 clinvar	12 clinvar	2 clinvar	154
nonsense	11 clinvar	9 clinvar	2 clinvar			22
start loss						0
frameshift	14 clinvar	18 clinvar	2 clinvar			34
splice donor/acceptor (+/-2bp)		2 clinvar	2 clinvar			4
Total	25	29	152	189	3	398

Highest pathogenic variant AF is 0.00002044488

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_033159.4	RefSeq	NP_149349.2	3	MANE Select
ENST00000395144.7	Ensembl	ENSP00000378576.2	3	MANE Select
NM_153281.2	RefSeq	NP_695013.1	3	Standard
NM_153282.3	RefSeq	NP_695014.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)
Glycosaminoglycan degradation - Homo sapiens (human)
Metabolism of carbohydrates
CS/DS degradation
Chondroitin sulfate/dermatan sulfate metabolism

Biological Process

response to reactive oxygen species
carbohydrate metabolic process
inflammatory response
response to virus
positive regulation of epithelial cell migration

Molecular Function

virus receptor activity
hyalurononglucosaminidase activity
transcription factor binding
hyaluronan synthase activity

Cellular Component

extracellular space
cytoplasm
lysosome
cytoplasmic vesicle
hyaluranon cable

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000266031
Coding exons: 3
Length: 12493
Individuals with no LoFs: 125711
Homozygous LoFs: 0
Heterozygous LoFs: 37
Defined: 125748
p: 0.000147

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.315	252	266	0.946	0.0000173	2812
Missense (PolyPhen)		93	98.118	0.94784		1105
Synonymous	0.00526	108	108	0.999	0.00000642	926
Loss of Function	1.52	8	14.2	0.564	6.25e-7	144

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.00026	0.00026	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May have a role in promoting tumor progression. May block the TGFB1-enhanced cell growth. {ECO:0000269|PubMed:12084718}.;

Intolerance Scores

LoFtool: 0.716
RVIS EVS: 0.11
RVIS percentile EVS: 62

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0278

Gene Damage Prediction

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