NM_000263.4(NAGLU):c.1834A>G (p.Ser612Gly) AND Mucopolysaccharidosis, MPS-III-B

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Apr 22, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000625994.11

Allele description [Variation Report for NM_000263.4(NAGLU):c.1834A>G (p.Ser612Gly)]

NM_000263.4(NAGLU):c.1834A>G (p.Ser612Gly)

Gene:

NAGLU:N-acetyl-alpha-glucosaminidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.2

Genomic location:

Preferred name:

NM_000263.4(NAGLU):c.1834A>G (p.Ser612Gly)

HGVS:

NC_000017.11:g.42543840A>G
NG_011552.1:g.12908A>G
NM_000263.4:c.1834A>GMANE SELECT
NP_000254.2:p.Ser612Gly
NC_000017.10:g.40695858A>G
NM_000263.3:c.1834A>G
p.S612G

Protein change:

S612G

Links:

dbSNP: rs148881970

NCBI 1000 Genomes Browser:

rs148881970

Molecular consequence:

NM_000263.4:c.1834A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Mucopolysaccharidosis, MPS-III-B (MPS3B)
Synonyms:: N-ACETYL-ALPHA-D-GLUCOSAMINIDASE DEFICIENCY; NAGLU DEFICIENCY; SANFILIPPO SYNDROME B; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009656; MedGen: C0086648; OMIM: 252920

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000746600	Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 9, 2017)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000914767	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Nov 1, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20040070, 9443875, 21712855, 20852935 Citation Link,
SCV001463392	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002102467	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 25, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005397724	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 22, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 29979746, 34743503, 20852935, 9443875, 21712855, 26907177, 28751108, 20040070, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
White	paternal	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Utilizing ExAC to assess the hidden contribution of variants of unknown significance to Sanfilippo Type B incidence.

Clark WT, Yu GK, Aoyagi-Scharber M, LeBowitz JH.

PLoS One. 2018;13(7):e0200008. doi: 10.1371/journal.pone.0200008.

PubMed [citation]

PMID:: 29979746
PMCID:: PMC6034809

Mucopolysaccharidosis III: Molecular basis and treatment.

Spahiu L, Behluli E, Peterlin B, Nefic H, Hadziselimovic R, Liehr T, Temaj G.

Pediatr Endocrinol Diabetes Metab. 2021;27(3):201-208. doi: 10.5114/pedm.2021.109270. Review.

PubMed [citation]

PMID:: 34743503
PMCID:: PMC10228206

See all PubMed Citations (9)

Details of each submission

From Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV000746600.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	White	1	not provided	not provided	clinical testing (GTR000553916.1)	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	yes	not provided	not provided	not provided	(GTR000553916.1)	1	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000914767.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The NAGLU c.1834A>G (p.Ser612Gly) variant has been reported in four studies and in a total of 11 probands with mucopolysaccharidosis including ten probands in a compound heterozygous state and one proband in a homozygous state (Zhao et al. 1998; Verhoeven et al. 2010; Valstar et al. 2010; Selmer et al. 2012). Segregation analysis confirmed co-segregation with disease in a clear autosomal recessive inheritance pattern in two families (Zhao et al. 1998; Selmer et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.00022 in the European (non-Finnish) population of the Exome Aggregation Consortium. Two studies demonstrated deficient alpha-N-acetyl glucosaminidase (NAGLU) enzyme activity in cultured fibroblasts from affected subjects (Verhoeven et al. 2010; Selmer et al. 2012). In five of the six families reported, this variant was associated with an attenuated phenotype of MPS IIIB with a slower progression of disease. Based on the collective evidence the p.Ser612Gly variant is classified as a pathogenic variant for mucopolysaccharidosis type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001463392.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV002102467.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center, SCV005397724.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence variant is a single nucleotide substitution (A>G) at position 1834 of the coding sequence of the NAGLU gene that results in a serine to glycine amino acid change at residue 612 of the N-acetyl-alpha-glucosaminidase protein. The 612 residue falls in the alpha-N-acetylglucosaminidase domain (UniProt). This is a previously reported variant (ClinVar 522823) that is one of the most commonly observed variants in individuals affected by attenuated mucopolysaccharidosis type IIIB (PMID: 34743503, 9443875, 20852935, 20040070, 26907177). In addition, this variant, while in the compound heterozygous state, cosegregates with attenuated mucopolysaccharidosis type IIIB in a family with four affected siblings (PMID: 21712855). This variant is present in 32 of 373546 alleles (0.0086%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Ser612 residue at this position is highly conserved across the vertebrate species examined. In addition, the enzymatic activity of the protein generated from this variant in transfected fibroblasts is significantly reduced relative to the wildtype protein (PMID: 26907177, 29979746, 28751108). Based upon the evidence, we consider this a pathogenic variant. ACMG Criteria: PM3, PP1, PP3, PS3, PS4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 6, 2025

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