GeneBe

SGSH

protein-coding

N-sulfoglucosamine sulfohydrolase, the group of Sulfatases

Gene summary

This gene encodes the enzyme sulfamidase; one of several enzymes involved in the lysosomal degradation of heparan sulfate. Mutations in this gene are associated with the lysosomal storage disease mucopolysaccaridosis IIIA, also known as Sanfilippo syndrome A, which results from impaired degradation of heparan sulfate. Transcripts of varying sizes have been reported but their biological validity has not been determined. [provided by RefSeq, Jun 2017]

MANE transcript

NM_000199.5

Inheritance

AD, AR

ClinVar variants

P:253U:311B:361

Top phenotype

Mucopolysaccharidosis type IIIA (Sanfilippo syndrome A)

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr17:80,206,716-80,220,923

External References & Databases

Ensembl (ENSG00000181523)NCBI Gene (6448)OMIM (605270)HGNC:10818GenCCUniProt (P51688)AlphaFoldClinVar (SGSH)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~14.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mucopolysaccharidosis type 3ADEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009655

Submitter: Ambry Genetics

mucopolysaccharidosis type 3ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009655

Submitter: PanelApp Australia

mucopolysaccharidosis type 3ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009655

Submitter: Myriad Women's Health

mucopolysaccharidosis type 3ASUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009655

Submitter: Orphanet

mucopolysaccharidosis type 3ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009655

Submitter: Labcorp Genetics (formerly Invitae)

mucopolysaccharidosis type 3ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009655

Submitter: Natera

mucopolysaccharidosis type 3ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009655

Submitter: G2P

mucopolysaccharidosis type 3ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009655

Submitter: ClinGen

The relationship between the SGSH gene and mucopolysaccharidosis type IIIA (MPS IIIA), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of April 30, 2022. SGSH encodes N-sulfoglucosamine sulfohydrolase, a lysosomal enzyme that involved in the degradation of heparan sulfate, through catalyzing the release of the sulfate groups linked to the amino group of glucosamine (PMID: 7493035). SGSH deficiency, which is present among individuals with MPS type IIIA, leads to accumulation of incompletely degraded oligosaccharides in lysosomes in the brain and other tissues, resulting in neurodegeneration with variable extra-neurologic manifestations (PMID: 18392742) The disease mechanism of MPS IIIA is loss of function. MPS IIIA was first reported in 1971 (PMID: 4252428) and the first report of biallelic variants in SGSH among patients with MPS IIIA was published in 1995 (PMID: 7493035). Since then, at least 68 unique variants have been identified (PMID: 11668611). Both case-level (genetic) and experimental evidence support the relationship between MPS IIIA and SGSH. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants. In total, 10 variants from five probands in five publications were curated (PMID: 9158154, PMID: 21671382, PMID: 15146460, PMID: 27590925, PMID: 11343308); although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached. Experimental evidence for the relationship between SGHS and MPS IIIA includes the biochemical function of the gene product (the MPS IIIA enzyme) being consistent with the clinical and biochemical findings identified individuals with MPS IIIA (PMID: 7493035, PMID: 18392742), the biochemical and clinical features of a mouse animal model homozygous for the p.D31N variant (PMID: 11181566, PMID: 15698885, PMID: 17913701), and the impact of hematopoietic stem cell transplant therapy in a MPS IIIA mouse model (PMID: 22547151). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached. In sum, SGSH is definitively associated with MPS type IIIA. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time.

mucopolysaccharidosis type 3ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009655

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Mucopolysaccharidosis type IIIA (Sanfilippo syndrome A)AR

Manifestation: Biochemical; Neurologic

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

Comments: BMT has been described, but was not reported to have a beneficial effect on prognosis

Refs: 4252428; 6796310; 7856659; 7493035; 9158154; 9401012; 9554748; 9727849; 9950362; 10518291; 10727844; 11668611; 12000360; 12702166; 15637719; 21061399; 28595941Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SGSH variants in ClinVar

20 Conditions Cataloged
Mucopolysaccharidosis, MPS-III-ATotal: 1050
not providedTotal: 163
not specifiedTotal: 119
SGSH-related disorderTotal: 84
Inborn genetic diseasesTotal: 81
MucopolysaccharidosisTotal: 6
Sanfilippo syndromeTotal: 6
Intellectual disabilityTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000199.5. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
11
clinvar
334
clinvar
1
clinvar
 347
missense
11
clinvar
84
clinvar
295
clinvar
24
clinvar
2
clinvar
 416
nonsense
21
clinvar
29
clinvar
1
clinvar
 51
start loss
2
clinvar
3
clinvar
 5
frameshift
37
clinvar
49
clinvar
2
clinvar
 88
splice donor/acceptor (+/-2bp)
1
clinvar
15
clinvar
2
clinvar
 18
Total721813113583925

Highest pathogenic variant AF is 0.0005178793

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000199.5RefSeqNP_000190.18MANE Select
ENST00000326317.11EnsemblENSP00000314606.68MANE Select
NM_001352921.3RefSeqNP_001339850.18Standard
NM_001352922.2RefSeqNP_001339851.19Standard

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
  • HS-GAG degradation
  • Heparan sulfate/heparin (HS-GAG) metabolism

Biological Process

  • glycosaminoglycan catabolic process
  • heparan sulfate proteoglycan catabolic process

Molecular Function

  • sulfuric ester hydrolase activity
  • N-sulfoglucosamine sulfohydrolase activity
  • metal ion binding

Cellular Component

  • lysosome
  • lysosomal lumen
  • extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000326317
Coding exons
8
Length
14208
Individuals with no LoFs
125575
Homozygous LoFs
0
Heterozygous LoFs
58
Defined
125633
p
0.000231
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.05383363331.010.00002523231
Missense (PolyPhen)123135.530.907521336
Synonymous-0.9071661521.090.00001291021
Loss of Function2.241021.10.4740.00000101214

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.000410.00040rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish0.000360.00032rare
European (Non-Finnish)0.000270.00026rare
South Asian0.0000650.000065rare
Other0.000330.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Catalyzes a step in lysosomal heparan sulfate degradation. {ECO:0000269|PubMed:15146460, ECO:0000269|PubMed:24816101, ECO:0000269|PubMed:7493035}.;
Disease
DISEASE: Mucopolysaccharidosis 3A (MPS3A) [MIM:252900]: A severe form of mucopolysaccharidosis type 3, an autosomal recessive lysosomal storage disease due to impaired degradation of heparan sulfate. MPS3 is characterized by severe central nervous system degeneration, but only mild somatic disease. Onset of clinical features usually occurs between 2 and 6 years; severe neurologic degeneration occurs in most patients between 6 and 10 years of age, and death occurs typically during the second or third decade of life. MPS3A is characterized by earlier onset, rapid progression of symptoms and shorter survival. {ECO:0000269|PubMed:11182930, ECO:0000269|PubMed:11793481, ECO:0000269|PubMed:12000360, ECO:0000269|PubMed:12702166, ECO:0000269|PubMed:15146460, ECO:0000269|PubMed:15637719, ECO:0000269|PubMed:15902564, ECO:0000269|PubMed:16311287, ECO:0000269|PubMed:17128482, ECO:0000269|PubMed:18407553, ECO:0000269|PubMed:21671382, ECO:0000269|PubMed:28101780, ECO:0000269|PubMed:9158154, ECO:0000269|PubMed:9285796, ECO:0000269|PubMed:9401012, ECO:0000269|PubMed:9554748, ECO:0000269|PubMed:9744479}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.175

Intolerance Scores

LoFtool
0.137
RVIS EVS
0.34
RVIS percentile EVS
73.7

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.320

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.