NM_000263.4(NAGLU):c.700C>T (p.Arg234Cys) AND Mucopolysaccharidosis, MPS-III-B

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Mar 25, 2022
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:: RCV000001638.18

Allele description [Variation Report for NM_000263.4(NAGLU):c.700C>T (p.Arg234Cys)]

NM_000263.4(NAGLU):c.700C>T (p.Arg234Cys)

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.700C>T (p.Arg234Cys)

HGVS:

NC_000017.11:g.42538691C>T
NG_011552.1:g.7759C>T
NM_000263.4:c.700C>TMANE SELECT
NP_000254.2:p.Arg234Cys
NC_000017.10:g.40690709C>T
NM_000263.3:c.700C>T
P54802:p.Arg234Cys

Protein change:

R234C; ARG234CYS

Links:

UniProtKB: P54802#VAR_054710; OMIM: 609701.0013; dbSNP: rs104894601

NCBI 1000 Genomes Browser:

rs104894601

Molecular consequence:

NM_000263.4:c.700C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Mucopolysaccharidosis, MPS-III-B (MPS3B)
Synonyms:: NAGLU DEFICIENCY; Mucopoly-saccharidosis type 3B; 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
SCV000021794	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 2008)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 9832037, 18218046
SCV000919840	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 20, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18218046, 9832037, 11286389 Citation Link,
SCV001140445	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001463384	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002318971	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 25, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9832037, 18218046, 23380547, 11286389, 30070758, 25741868

Help

Summary from all submissions

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

Citations

PubMed

Identification of 12 novel mutations in the alpha-N-acetylglucosaminidase gene in 14 patients with Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB).

Beesley CE, Young EP, Vellodi A, Winchester BG.

J Med Genet. 1998 Nov;35(11):910-4.

PubMed [citation]

PMID:: 9832037
PMCID:: PMC1051483

Molecular analysis of mucopolysaccharidosis type IIIB in Portugal: evidence of a single origin for a common mutation (R234C) in the Iberian Peninsula.

Mangas M, Nogueira C, Prata MJ, Lacerda L, Coll MJ, Soares G, Ribeiro G, Amaral O, Ferreira C, Alves C, Coutinho MF, Alves S.

Clin Genet. 2008 Mar;73(3):251-6. doi: 10.1111/j.1399-0004.2007.00951.x. Epub 2008 Jan 23.

PubMed [citation]

PMID:: 18218046

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000021794.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In patients with mucopolysaccharidosis type IIIB (MPS3B; 252920), Beesley et al. (1998) identified a C-to-T transition in the NAGLU gene, resulting in an arg234-to-cys (R234C) substitution.

Mangas et al. (2008) identified the R234C mutation in 5 of 11 Portuguese patients with MPS3B. The mutation was the most common identified in this population, accounting for 32% of mutant alleles. Haplotype analysis showed that the R234C mutation arose on a founder haplotype common to both Spanish and Portuguese individuals. Mangas et al. (2008) postulated that the mutation had a single and relatively recent origin in the Iberian peninsula.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919840.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: The NAGLU c.700C>T (p.Arg234Cys) variant located in the alpha-n-acetylglucosaminidase, tim-barrel domain (via InterPro) involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 10/276804 control chromosomes (gnomAD and publication controls) at a frequency of 0.0000361, which does not exceed the estimated maximal expected allele frequency of a pathogenic NAGLU variant (0.0025). Multiple publications have cited the variant in compound heterozygote and homozygote MPS IIIB pts and found NAGLU activity to be significantly decreased (Mangas_2008). In addition, a reputable database, OMIM classifies the variant as "pathogenic." Taken together, this variant is classified as pathogenic.

#	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 Mendelics, SCV001140445.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001463384.1

#	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 DASA, SCV002318971.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

The c.700C>T;p.(Arg234Cys) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 1572; PMID: 9832037; PMID: 30070758; PMID: 11286389; PMID: 18218046; PMID: 23380547) -PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (NAGLU) - PM1. The variant is present at low allele frequencies population databases (rs104894601 – gnomAD 0.0003188%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. The p.(Arg234Cys) was detected in trans with a pathogenic variant (PMID: 11286389; PMID: 30070758) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic

#	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		1	not provided	not provided	not provided

Last Updated: May 7, 2024

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