ClinVar Genomic variation as it relates to human health
NM_000512.5(GALNS):c.1559G>A (p.Trp520Ter)
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_000512.5(GALNS):c.1559G>A (p.Trp520Ter)
Variation ID: 93171 Accession: VCV000093171.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q24.3 16: 88814449 (GRCh38) [ NCBI UCSC ] 16: 88880857 (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 Jun 28, 2015 Feb 14, 2024 Jun 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000512.5:c.1559G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000503.1:p.Trp520Ter nonsense NM_001323543.2:c.1004G>A NP_001310472.1:p.Trp335Ter nonsense NM_001323544.2:c.1577G>A NP_001310473.1:p.Trp526Ter nonsense NC_000016.10:g.88814449C>T NC_000016.9:g.88880857C>T NG_008013.1:g.2486G>A NG_008667.1:g.47518G>A - Protein change
- W520*, W335*, W526*
- Other names
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- Canonical SPDI
- NC_000016.10:88814448: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), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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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GALNS | - | - |
GRCh38 GRCh37 |
1054 | 1341 |
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 (1) |
criteria provided, single submitter
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Dec 14, 2012 | RCV000174686.12 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 30, 2023 | RCV001578462.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 8, 2022 | RCV002509202.8 |
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
(Dec 14, 2012)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000226034.5
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
Number of individuals with the variant: 1
Sex: mixed
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Likely pathogenic
(Feb 01, 2021)
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criteria provided, single submitter
Method: research
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Mucopolysaccharidosis, MPS-IV-A
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova
Accession: SCV001547996.3
First in ClinVar: Aug 27, 2021 Last updated: Oct 30, 2021 |
Comment:
Nonsense variant (PVS1_moderate); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); very low frequency in … (more)
Nonsense variant (PVS1_moderate); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); very low frequency in gnomAD v2.1.1 (PM2_moderate); (less)
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Pathogenic
(Dec 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Morquio syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002819340.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: GALNS c.1559G>A (p.Trp520X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: GALNS c.1559G>A (p.Trp520X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported in HGMD in association wtih Mucopolysaccharidosis IVa. The variant allele was found at a frequency of 5.9e-06 in 170644 control chromosomes. c.1559G>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (e.g. Terzioglu_2002, Morrone_2014, Szklanny_2018, Jezela_Stankek_2019), and the same protein variant, p.W520X, has also been reported in individuals with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (e.g. He_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) have classified, with one submitter classifying the variant as pathogenic and the other classifying the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-IV-A
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002044993.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Pathogenic
(Jun 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-IV-A
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004297051.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD … (more)
The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 24035930, 24726177). ClinVar contains an entry for this variant (Variation ID: 93171). This variant disrupts a region of the GALNS protein in which other variant(s) (p.Trp520Arg) have been determined to be pathogenic (PMID: 34472180). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Trp520*) in the GALNS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3 amino acid(s) of the GALNS protein. (less)
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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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The youngest pair of siblings with Mucopolysaccharidosis type IVA to receive enzyme replacement therapy to date: A case report. | Frigeni M | American journal of medical genetics. Part A | 2021 | PMID: 34472180 |
Molecular basis of mucopolysaccharidosis IVA (Morquio A syndrome): A review and classification of GALNS gene variants and reporting of 68 novel variants. | Zanetti A | Human mutation | 2021 | PMID: 34387910 |
Novel data on growth phenotype and causative genotypes in 29 patients with Morquio (Morquio-Brailsford) syndrome from Central-Eastern Europe. | Jezela-Stanek A | Journal of applied genetics | 2019 | PMID: 30927141 |
Voice alterations in patients with Morquio A syndrome. | Szklanny K | Journal of applied genetics | 2018 | PMID: 29275451 |
Molecular testing of 163 patients with Morquio A (Mucopolysaccharidosis IVA) identifies 39 novel GALNS mutations. | Morrone A | Molecular genetics and metabolism | 2014 | PMID: 24726177 |
Molecular genetic assay of mucopolysaccharidosis IVA in South China. | He D | Gene | 2013 | PMID: 24035930 |
Molecular analysis of Turkish mucopolysaccharidosis IVA (Morquio A) patients: identification of novel mutations in the N-acetylgalactosamine-6-sulfate sulfatase (GALNS) gene. | Terzioglu M | Human mutation | 2002 | PMID: 12442278 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GALNS | - | - | - | - |
Text-mined citations for rs372893383 ...
HelpRecord last updated Jun 02, 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.