ClinVar Genomic variation as it relates to human health
NM_000263.4(NAGLU):c.1693C>T (p.Arg565Trp)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000263.4(NAGLU):c.1693C>T (p.Arg565Trp)
Variation ID: 1567 Accession: VCV000001567.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.2 17: 42543699 (GRCh38) [ NCBI UCSC ] 17: 40695717 (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 May 18, 2015 Feb 28, 2024 Dec 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000263.4:c.1693C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000254.2:p.Arg565Trp missense NC_000017.11:g.42543699C>T NC_000017.10:g.40695717C>T NG_011552.1:g.12767C>T P54802:p.Arg565Trp - Protein change
- R565W
- Other names
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- Canonical SPDI
- NC_000017.11:42543698: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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00010
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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NAGLU | - | - |
GRCh38 GRCh37 |
1051 | 1271 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000001633.12 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 9, 2023 | RCV001223228.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 14, 2022 | RCV002269255.2 |
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
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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
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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
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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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Pathogenic
(Oct 02, 2017)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-III-B
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919839.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The NAGLU c.1693C>T (p.Arg565Trp) variant located in the Alpha-N-acetylglucosaminidase, C-terminal domain (IPR024732) (InterPro) causes a missense change involving a conserved nucleotide and 4/4 … (more)
Variant summary: The NAGLU c.1693C>T (p.Arg565Trp) variant located in the Alpha-N-acetylglucosaminidase, C-terminal domain (IPR024732) (InterPro) causes a missense change involving a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional enzymatic studies showed very low to no alpha-N-acetyl-glucosaminidase activity in peripheral leukocytes and cultured fibroblasts of homozygotes and compound heterozygotes (Tanaka_2002 and Shi_2014). The variant was found in 10/274834 control chromosomes (gnomAD) at a frequency of 0.0000364, which does not exceed the estimated maximal expected allele frequency of a pathogenic NAGLU variant (0.0025). This variant was reported in multiple patients diagnosed with Sanfilippo syndrome (mucopolysaccharidosis IIIB), associated with a severe phenotype (Beesley_2005, Weber_Genet_1999, Shi_2014). In addition, a clinical diagnostic laboratory and a reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Nov 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-III-B
Charcot-Marie-Tooth disease axonal type 2V
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809439.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jul 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002552800.2
First in ClinVar: Jul 29, 2022 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23380547, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23380547, 20852935, 18218046, 25466957, 9832037, 11668611, 10094189, 11286389, 29979746, 34440436, 31589614, 32014045) (less)
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Pathogenic
(Dec 09, 2023)
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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
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001395367.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 565 of the NAGLU protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 565 of the NAGLU protein (p.Arg565Trp). This variant is present in population databases (rs104894597, gnomAD 0.04%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIB (PMID: 9832037, 12202988, 25466957). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1567). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg565 amino acid residue in NAGLU. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9950362, 20852935, 28751108). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-III-B
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000402914.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The NAGLU c.1693C>T (p.Arg565Trp) variant has been reported to account for 3.4% of variant alleles in individuals with mucopolysaccharidosis type III and is associated with … (more)
The NAGLU c.1693C>T (p.Arg565Trp) variant has been reported to account for 3.4% of variant alleles in individuals with mucopolysaccharidosis type III and is associated with an attenuated phenotype (Yogalingham et al. 2001). The p.Arg565Trp variant has been reported in ten studies and is found in a total of 17 individuals including in four individuals in a homozygous state, in 11 individuals (including three sibling pairs) in a compound heterozygous state, and in two individuals in a heterozygous state (Beesley et al. 1998; Weber et al. 1999; Col et al. 2001; Tanaka et al. 2002; Lee-Chen et al. 2002; Beesley et al. 2005; Mangas et al. 2008; Valstar et al. 2010; Tang et al. 2013; Shi et al. 2014). The p.Arg565Trp variant was absent from 474 ethnically matched control chromosomes and is reported at a frequency of 0.00035 in the East Asian population of the Exome Aggregation Consortium. The p.Arg565Trp variant showed a drastic reduction in NAGLU enzyme activity despite normal mRNA levels in four studies (Lee-Chen et al. 2002; Mangas et al. 2008; Tang et al. 2013; Shi et al. 2014). Structural modelling showed that the p.Arg565Trp variant is located at the alpha-helical domain next to the enzyme binding site (Shi et al. 2014). Based on the collective evidence, the p.Arg565Trp variant is classified as pathogenic for mucopolysaccharidosis type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-III-B
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001140449.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Mar 07, 2017)
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no assertion criteria provided
Method: clinical testing
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Mucopolysaccharidosis, MPS-III-B
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000790179.2
First in ClinVar: Oct 11, 2015 Last updated: Jun 02, 2019 |
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Pathogenic
(Jan 01, 1999)
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no assertion criteria provided
Method: literature only
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MUCOPOLYSACCHARIDOSIS, TYPE IIIB
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021789.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 07, 2021 |
Comment on evidence:
Weber et al. (1999) found that an arg565-to-trp (R565W) missense mutation accounted for approximately 6% of the mutant alleles in Australasian patients with Sanfilippo syndrome … (more)
Weber et al. (1999) found that an arg565-to-trp (R565W) missense mutation accounted for approximately 6% of the mutant alleles in Australasian patients with Sanfilippo syndrome B (MPS3B; 252920). (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
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Natera, Inc.
Accession: SCV001463390.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Processing of mutant N-acetyl-α-glucosaminidase in mucopolysaccharidosis type IIIB fibroblasts cultured at low temperature. | Meijer OLM | Molecular genetics and metabolism | 2017 | PMID: 28751108 |
Residual N-acetyl-α-glucosaminidase activity in fibroblasts correlates with disease severity in patients with mucopolysaccharidosis type IIIB. | Meijer OLM | Journal of inherited metabolic disease | 2016 | PMID: 26907177 |
"Genotype-first" approaches on a curious case of idiopathic progressive cognitive decline. | Shi L | BMC medical genomics | 2014 | PMID: 25466957 |
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 |
Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype. | Valstar MJ | Journal of inherited metabolic disease | 2010 | PMID: 20852935 |
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 |
Molecular defects in Sanfilippo syndrome type B (mucopolysaccharidosis IIIB). | Beesley CE | Journal of inherited metabolic disease | 2005 | PMID: 16151907 |
Molecular analysis of the alpha-N-acetylglucosaminidase gene in seven Japanese patients from six unrelated families with mucopolysaccharidosis IIIB (Sanfilippo type B), including two novel mutations. | Tanaka A | Journal of human genetics | 2002 | PMID: 12202988 |
Identification and characterisation of mutations underlying Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB). | Lee-Chen GJ | Journal of medical genetics | 2002 | PMID: 11836372 |
Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications. | Yogalingam G | Human mutation | 2001 | PMID: 11668611 |
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 |
Sanfilippo type B syndrome (mucopolysaccharidosis III B): allelic heterogeneity corresponds to the wide spectrum of clinical phenotypes. | Weber B | European journal of human genetics : EJHG | 1999 | PMID: 10094189 |
Mucopolysaccharidosis type IIIB (Sanfilippo B): identification of 18 novel alpha-N-acetylglucosaminidase gene mutations. | Bunge S | Journal of medical genetics | 1999 | PMID: 9950362 |
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 |
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Text-mined citations for rs104894597 ...
HelpRecord last updated Sep 29, 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.