Variant summary: The NAGLU c.1694G>A (p.Arg565Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). Arg565 is highly conserved across species, and two other mutations have been reported at the Arg565 codon (R565Q, R565P) (Beesley et al 1998; Bunge et al 1999; Weber et al 1999), which suggests that this codon is a mutational hotspot in the NAGLU gene. This variant was found in 4/115194 control chromosomes at a frequency of 0.0000347, which does not exceed the estimated maximal expected allele frequency of a pathogenic NAGLU variant (0.0025). The variant has been identified in multiple MPS3B patients in compound heterozygous state and has been shown to co-segregate with disease in at least one family (Tang_CCA_2013). Compound heterozygous patients have been shown to have <10% of normal NAGLU activity. In addition, OMIM classified this 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.1694G>A (p.Arg565Gln)
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.
(9)
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
9
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.1694G>A (p.Arg565Gln)
Variation ID: 30795 Accession: VCV000030795.39
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q21.2 17: 42543700 (GRCh38) [ NCBI UCSC ] 17: 40695718 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 20, 2024 May 6, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000263.4:c.1694G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000254.2:p.Arg565Gln missense NC_000017.11:g.42543700G>A NC_000017.10:g.40695718G>A NG_011552.1:g.12768G>A P54802:p.Arg565Gln - Protein change
- R565Q
- Other names
- -
- Canonical SPDI
- NC_000017.11:42543699:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00006
- 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 |
1055 | 1276 | |
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
|
May 6, 2024 | RCV000023780.11 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 8, 2024 | RCV000433629.25 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 17, 2016 | RCV000590258.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 29, 2024 | RCV001043861.7 |
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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|---|---|---|---|---|---|
|
Pathogenic
(Jun 17, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Sanfilippo syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696367.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The NAGLU c.1694G>A (p.Arg565Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured … (more)
Variant summary: The NAGLU c.1694G>A (p.Arg565Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). Arg565 is highly conserved across species, and two other mutations have been reported at the Arg565 codon (R565Q, R565P) (Beesley et al 1998; Bunge et al 1999; Weber et al 1999), which suggests that this codon is a mutational hotspot in the NAGLU gene. This variant was found in 4/115194 control chromosomes at a frequency of 0.0000347, which does not exceed the estimated maximal expected allele frequency of a pathogenic NAGLU variant (0.0025). The variant has been identified in multiple MPS3B patients in compound heterozygous state and has been shown to co-segregate with disease in at least one family (Tang_CCA_2013). Compound heterozygous patients have been shown to have <10% of normal NAGLU activity. In addition, OMIM classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
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: SCV001207628.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 565 of the NAGLU protein (p.Arg565Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 565 of the NAGLU protein (p.Arg565Gln). This variant is present in population databases (rs104894598, gnomAD 0.009%). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 9950362, 20852935, 23380547, 28751108). ClinVar contains an entry for this variant (Variation ID: 30795). 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: 10094189, 15933803, 23430803). 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)
|
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: curation
|
Mucopolysaccharidosis, MPS-III-B
Affected status: no
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051873.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Mar 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000521202.5
First in ClinVar: Mar 08, 2017 Last updated: Sep 29, 2024 |
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein … (more)
Not observed at a significant frequency in large population cohorts (gnomAD); 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: 11668611, 20852935, 9950362, 16151907, 21937992, 26907177, 21204211, 23380547, 28751108, 29979746, 30426380, 23430803, 15933803, 15300983, 10094189, 28844463, 28101780, 31589614, 33747789, 33552644) (less)
|
|
|
Pathogenic
(May 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV005046814.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
Comment:
A homozygous variant in exon 6 of the NAGLU gene that results in the amino acid substitution of glutamine for arginine at codon 565 was … (more)
A homozygous variant in exon 6 of the NAGLU gene that results in the amino acid substitution of glutamine for arginine at codon 565 was detected. The observed variant c.1694G>A has not been reported in the 1000 genomes database and has MAF of 0.0044% in the gnomAD database. The in silico predictions is damaging by MutationTaster and SIFT, Polyphen2 and DANN. In summary, the variant meets our criteria to be classified as pathogenic. (less)
Age: 0-9 years
Sex: female
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
|
|
|
Pathogenic
(Nov 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246601.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Sep 29, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-B
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000788474.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 23, 2019 |
|
|
|
Pathogenic
(Sep 21, 2011)
|
no assertion criteria provided
Method: literature only
|
MUCOPOLYSACCHARIDOSIS, TYPE IIIB
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000045071.5
First in ClinVar: Apr 04, 2013 Last updated: Aug 03, 2021 |
Comment on evidence:
In 3 affected children in family 8600486 with severe intellectual disability, autism spectrum disorder, and coarse facial features, diagnosed as mucopolysaccharidosis type IIIB (MPS3B; 252920), … (more)
In 3 affected children in family 8600486 with severe intellectual disability, autism spectrum disorder, and coarse facial features, diagnosed as mucopolysaccharidosis type IIIB (MPS3B; 252920), Najmabadi et al. (2011) identified a homozygous G-to-A transition in the NAGLU gene at genomic coordinate chr17:37949244 (NCBI36), resulting in an arg565-to-gln (R565Q) substitution. Their parents, who were first cousins once removed, were carriers. (less)
|
|
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Pathogenic
(Aug 17, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Mucopolysaccharidosis type IIIB
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002093276.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 565 of the NAGLU protein (p.Arg565Gln). This variant is present in population databases (rs104894598, gnomAD 0.009%). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 9950362, 20852935, 23380547, 28751108). ClinVar contains an entry for this variant (Variation ID: 30795). 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: 10094189, 15933803, 23430803). 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.
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); 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: 11668611, 20852935, 9950362, 16151907, 21937992, 26907177, 21204211, 23380547, 28751108, 29979746, 30426380, 23430803, 15933803, 15300983, 10094189, 28844463, 28101780, 31589614, 33747789, 33552644)
Comment:
A homozygous variant in exon 6 of the NAGLU gene that results in the amino acid substitution of glutamine for arginine at codon 565 was detected. The observed variant c.1694G>A has not been reported in the 1000 genomes database and has MAF of 0.0044% in the gnomAD database. The in silico predictions is damaging by MutationTaster and SIFT, Polyphen2 and DANN. In summary, the variant meets our criteria to be 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.1694G>A (p.Arg565Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). Arg565 is highly conserved across species, and two other mutations have been reported at the Arg565 codon (R565Q, R565P) (Beesley et al 1998; Bunge et al 1999; Weber et al 1999), which suggests that this codon is a mutational hotspot in the NAGLU gene. This variant was found in 4/115194 control chromosomes at a frequency of 0.0000347, which does not exceed the estimated maximal expected allele frequency of a pathogenic NAGLU variant (0.0025). The variant has been identified in multiple MPS3B patients in compound heterozygous state and has been shown to co-segregate with disease in at least one family (Tang_CCA_2013). Compound heterozygous patients have been shown to have <10% of normal NAGLU activity. In addition, OMIM classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 565 of the NAGLU protein (p.Arg565Gln). This variant is present in population databases (rs104894598, gnomAD 0.009%). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 9950362, 20852935, 23380547, 28751108). ClinVar contains an entry for this variant (Variation ID: 30795). 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: 10094189, 15933803, 23430803). 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.
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); 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: 11668611, 20852935, 9950362, 16151907, 21937992, 26907177, 21204211, 23380547, 28751108, 29979746, 30426380, 23430803, 15933803, 15300983, 10094189, 28844463, 28101780, 31589614, 33747789, 33552644)
Comment:
A homozygous variant in exon 6 of the NAGLU gene that results in the amino acid substitution of glutamine for arginine at codon 565 was detected. The observed variant c.1694G>A has not been reported in the 1000 genomes database and has MAF of 0.0044% in the gnomAD database. The in silico predictions is damaging by MutationTaster and SIFT, Polyphen2 and DANN. In summary, the variant meets our criteria to be classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Prevalence and Novel Mutations of Lysosomal Storage Disorders in United Arab Emirates : LSD in UAE. | Al-Jasmi FA | JIMD reports | 2013 | PMID: 23430803 |
| 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 |
| Deep sequencing reveals 50 novel genes for recessive cognitive disorders. | Najmabadi H | Nature | 2011 | PMID: 21937992 |
| Incidence and natural history of mucopolysaccharidosis type III in France and comparison with United Kingdom and Greece. | Héron B | American journal of medical genetics. Part A | 2011 | PMID: 21204211 |
| Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype. | Valstar MJ | Journal of inherited metabolic disease | 2010 | PMID: 20852935 |
| Sanfilippo type B syndrome: five patients with an R565P homozygous mutation in the alpha-N-acetylglucosaminidase gene from the Okinawa islands in Japan. | Chinen Y | Journal of human genetics | 2005 | PMID: 15933803 |
| Gene symbol: NAGLU. Disease: Sanfillipo syndrome B. | Villani GR | Human genetics | 2004 | PMID: 15300983 |
| 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 |
Text-mined citations for rs104894598 ...
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 Oct 20, 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.