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.
ClinVar Genomic variation as it relates to human health
NM_000263.4(NAGLU):c.700C>T (p.Arg234Cys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(6)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000263.4(NAGLU):c.700C>T (p.Arg234Cys)
Variation ID: 1572 Accession: VCV000001572.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.2 17: 42538691 (GRCh38) [ NCBI UCSC ] 17: 40690709 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 5, 2015 Feb 28, 2024 Oct 20, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000263.4:c.700C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000254.2:p.Arg234Cys missense NC_000017.11:g.42538691C>T NC_000017.10:g.40690709C>T NG_011552.1:g.7759C>T P54802:p.Arg234Cys - Protein change
- R234C
- Other names
- -
- Canonical SPDI
- NC_000017.11:42538690:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| NAGLU | - | - |
GRCh38 GRCh37 |
1053 | 1273 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 25, 2022 | RCV000001638.19 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 20, 2023 | RCV001203422.15 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(Nov 20, 2017)
|
criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-III-B
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919840.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
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 … (more)
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. (less)
|
|
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Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-B
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001140445.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Mar 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-B
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002318971.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
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; … (more)
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 (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
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Pathogenic
(Oct 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease axonal type 2V
Mucopolysaccharidosis, MPS-III-B
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001374588.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 234 of the NAGLU protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 234 of the NAGLU protein (p.Arg234Cys). This variant is present in population databases (rs104894601, gnomAD 0.02%). This missense change has been observed in individual(s) with NAGLU-related conditions (PMID: 9832037, 11286389, 18218046, 23380547, 30070758). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1572). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NAGLU protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Mucopolysaccharidosis type IIIB
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001463384.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
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Pathogenic
(Mar 01, 2008)
|
no assertion criteria provided
Method: literature only
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MUCOPOLYSACCHARIDOSIS, TYPE IIIB
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000021794.5
First in ClinVar: Apr 04, 2013 Last updated: Aug 07, 2021 |
Comment on evidence:
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) … (more)
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. (less)
|
Comment:
Comment:
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
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 234 of the NAGLU protein (p.Arg234Cys). This variant is present in population databases (rs104894601, gnomAD 0.02%). This missense change has been observed in individual(s) with NAGLU-related conditions (PMID: 9832037, 11286389, 18218046, 23380547, 30070758). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1572). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NAGLU protein function. For these reasons, this variant has been classified as Pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 234 of the NAGLU protein (p.Arg234Cys). This variant is present in population databases (rs104894601, gnomAD 0.02%). This missense change has been observed in individual(s) with NAGLU-related conditions (PMID: 9832037, 11286389, 18218046, 23380547, 30070758). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1572). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NAGLU protein function. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mucopolysaccharidosis III in Taiwan: Natural history, clinical and molecular characteristics of 28 patients diagnosed during a 21-year period. | Lin HY | American journal of medical genetics. Part A | 2018 | PMID: 30070758 |
| Mucopolysaccharidosis type IIIB mutations in Chinese patients: identification of two novel NAGLU mutations and analysis of two cases involving prenatal diagnosis. | Tang J | Clinica chimica acta; international journal of clinical chemistry | 2013 | PMID: 23380547 |
| Molecular analysis of mucopolysaccharidosis type IIIB in Portugal: evidence of a single origin for a common mutation (R234C) in the Iberian Peninsula. | Mangas M | Clinical genetics | 2008 | PMID: 18218046 |
| Allelic heterogeneity in Spanish patients with Sanfilippo disease type B. Identification of eight new mutations. | Coll MJ | Journal of inherited metabolic disease | 2001 | PMID: 11286389 |
| Identification of 12 novel mutations in the alpha-N-acetylglucosaminidase gene in 14 patients with Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB). | Beesley CE | Journal of medical genetics | 1998 | PMID: 9832037 |
Text-mined citations for rs104894601 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 03, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.