ClinVar Genomic variation as it relates to human health
NM_000263.4(NAGLU):c.1562C>T (p.Pro521Leu)
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.1562C>T (p.Pro521Leu)
Variation ID: 1566 Accession: VCV000001566.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.2 17: 42543568 (GRCh38) [ NCBI UCSC ] 17: 40695586 (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 May 26, 2024 Feb 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000263.4:c.1562C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000254.2:p.Pro521Leu missense NC_000017.11:g.42543568C>T NC_000017.10:g.40695586C>T NG_011552.1:g.12636C>T P54802:p.Pro521Leu - Protein change
- P521L
- Other names
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- Canonical SPDI
- NC_000017.11:42543567: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.
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00004
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 | ||
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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
Help
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 | 1270 |
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
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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/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Feb 8, 2024 | RCV000001632.10 | |
not provided (1) |
no classification provided
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- | RCV001030807.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 23, 2024 | RCV001043674.6 | |
Likely pathogenic (3) |
criteria provided, single submitter
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Mar 2, 2022 | RCV001729332.5 |
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
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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
(Feb 13, 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:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362135.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: NAGLU c.1562C>T (p.Pro521Leu) results in a non-conservative amino acid change located in the C-terminal domain of the encoded protein sequence. Five of five … (more)
Variant summary: NAGLU c.1562C>T (p.Pro521Leu) results in a non-conservative amino acid change located in the C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.6e-05 in 271726 control chromosomes (gnomAD). c.1562C>T has been reported in the literature in compound heterozygous and homozygous individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) (e.g. Zhao 1998, Beesley 2005, Valstar 2010). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Mar 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003816285.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Feb 08, 2024)
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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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Clinical Genomics Laboratory, Washington University in St. Louis
Accession: SCV005045188.1
First in ClinVar: May 26, 2024 Last updated: May 26, 2024 |
Comment:
The NAGLU c.1562C>T (p.Pro521Leu) variant has been reported in 13 individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) and is reported to segregate with … (more)
The NAGLU c.1562C>T (p.Pro521Leu) variant has been reported in 13 individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) and is reported to segregate with disease in nine individuals in two families (Beesley CE et al., PMID: 9832037; Valstar MJ et al., PMID: 20852935; Weber B et al., PMID: 10094189; Zhao HG et al., PMID: 9443875; Zheng Q et al., PMID: 28306536). Of those individuals, nine were compound heterozygous for the variant and a pathogenic/likely pathogenic variant was confirmed to be in trans (Valstar MJ et al., PMID: 20852935; Zhao HG et al., PMID: 9443875) and two individuals were homozygous for the variant (Beesley CE et al., PMID: 9832037; Weber B et al., PMID: 10094189). This variant is only observed on 7 out of 277,290 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to NAGLU function. This variant has been reported in the ClinVar database as a pathogenic or likely pathogenic germline variant by seven submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic. (less)
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Pathogenic
(Mar 09, 2022)
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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: SCV002813368.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 23, 2024)
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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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Invitae
Accession: SCV001207432.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 521 of the NAGLU protein (p.Pro521Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 521 of the NAGLU protein (p.Pro521Leu). This variant is present in population databases (rs104894595, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 9443875, 20852935, 28306536). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1566). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Jun 07, 2017)
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no assertion criteria provided
Method: curation
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Mucopolysaccharidosis, MPS-III-B
Affected status: no
Allele origin:
germline
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SingHealth Duke-NUS Institute of Precision Medicine
Accession: SCV000853170.1
First in ClinVar: Nov 25, 2018 Last updated: Nov 25, 2018 |
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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: SCV000021788.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 03, 2021 |
Comment on evidence:
Weber et al. (1999) found that a pro521-to-leu (P521L) missense mutation in the NAGLU gene accounted for approximately 6% of mutations in Australasian patients with … (more)
Weber et al. (1999) found that a pro521-to-leu (P521L) missense mutation in the NAGLU gene accounted for approximately 6% of mutations in Australasian patients with Sanfilippo syndrome B (MPS3B; 252920). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001980317.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001978741.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(Aug 25, 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: SCV002093272.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Mucopolysaccharidosis
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV001194296.2
First in ClinVar: Apr 06, 2020 Last updated: Oct 01, 2022 |
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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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Molecular defects identified by whole exome sequencing in a child with atypical mucopolysaccharidosis IIIB. | Zeng Q | Journal of pediatric endocrinology & metabolism : JPEM | 2017 | PMID: 28306536 |
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 (mucopolysaccharidosis III B): allelic heterogeneity corresponds to the wide spectrum of clinical phenotypes. | Weber B | European journal of human genetics : EJHG | 1999 | PMID: 10094189 |
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 |
Genotype-phenotype correspondence in Sanfilippo syndrome type B. | Zhao HG | American journal of human genetics | 1998 | PMID: 9443875 |
Text-mined citations for rs104894595 ...
HelpRecord last updated May 27, 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.