ClinVar Genomic variation as it relates to human health
NM_000199.5(SGSH):c.448C>T (p.Arg150Trp)
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.
Pathogenic(1); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000199.5(SGSH):c.448C>T (p.Arg150Trp)
Variation ID: 638088 Accession: VCV000638088.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80214673 (GRCh38) [ NCBI UCSC ] 17: 78188472 (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 Jul 29, 2019 Jun 17, 2024 Mar 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000199.5:c.448C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000190.1:p.Arg150Trp missense NM_000199.3:c.448C>T NM_001352921.3:c.448C>T NP_001339850.1:p.Arg150Trp missense NM_001352922.2:c.448C>T NP_001339851.1:p.Arg150Trp missense NR_148201.2:n.362C>T non-coding transcript variant NC_000017.11:g.80214673G>A NC_000017.10:g.78188472G>A NG_008229.1:g.10728C>T - Protein change
- R150W
- Other names
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- Canonical SPDI
- NC_000017.11:80214672:G:A
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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 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
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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SGSH | - | - |
GRCh38 GRCh38 GRCh37 |
995 | 1477 |
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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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Mar 18, 2024 | RCV000790554.15 |
Submissions - Germline
Classification
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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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Uncertain significance
(Jan 01, 2019)
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criteria provided, single submitter
Method: literature only
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Mucopolysaccharidosis, MPS-III-A
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova
Accession: SCV000929895.1
First in ClinVar: Jul 29, 2019 Last updated: Jul 29, 2019 |
Comment:
PM2: Very low frequency in ExAc. PP3:multiple lines of computational evidence supporting a deleterious effect (DANN, MutationTaster, GERP, SIFT)
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Likely pathogenic
(Nov 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-III-A
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002045103.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Likely pathogenic
(Sep 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-III-A
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002598580.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
Variant summary: SGSH c.448C>T (p.Arg150Trp) results in a non-conservative amino acid change located in the sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five … (more)
Variant summary: SGSH c.448C>T (p.Arg150Trp) results in a non-conservative amino acid change located in the sulfatase, N-terminal domain (IPR000917) 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 4e-06 in 250536 control chromosomes (gnomAD). c.448C>T has been reported in the literature as a biallelic genotype and in the heterozygous state in individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (e.g. Beesley_2000, Chabas_2001, Zanetti_2019, Kong_2020, Wijburg_2022). These data indicate that the variant is likely to be associated with disease. Other variants affecting the same amino acid residue (p.Arg150Gln, p.Arg150Gly) have been cited in ClinVar and/or HGDM as pathogenic/likely pathogenic and disease-associated. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have provided assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Oct 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-III-A
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001578965.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 150 of the SGSH protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 150 of the SGSH protein (p.Arg150Trp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 11182930, 30809705). ClinVar contains an entry for this variant (Variation ID: 638088). 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 SGSH protein function. This variant disrupts the p.Arg150 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9401012, 9554748, 9744479, 10727844, 11343308, 21061399, 21204211). 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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Likely pathogenic
(Mar 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-III-A
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004201069.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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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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An observational, prospective, multicenter, natural history study of patients with mucopolysaccharidosis type IIIA. | Wijburg FA | Molecular genetics and metabolism | 2022 | PMID: 34991944 |
Mucopolysaccharidosis III in Mainland China: natural history, clinical and molecular characteristics of 34 patients. | Kong W | Journal of pediatric endocrinology & metabolism : JPEM | 2020 | PMID: 32447333 |
Molecular diagnosis of patients affected by mucopolysaccharidosis: a multicenter study. | Zanetti A | European journal of pediatrics | 2019 | PMID: 30809705 |
A multiparametric computational algorithm for comprehensive assessment of genetic mutations in mucopolysaccharidosis type IIIA (Sanfilippo syndrome). | Ugrinov KG | PloS one | 2015 | PMID: 25807448 |
Structure of sulfamidase provides insight into the molecular pathology of mucopolysaccharidosis IIIA. | Sidhu NS | Acta crystallographica. Section D, Biological crystallography | 2014 | PMID: 24816101 |
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 IIIA: clinical spectrum and genotype-phenotype correlations. | Valstar MJ | Annals of neurology | 2010 | PMID: 21061399 |
Mutation and haplotype analyses in 26 Spanish Sanfilippo syndrome type A patients: possible single origin for 1091delC mutation. | Chabás A | American journal of medical genetics | 2001 | PMID: 11343308 |
Mutational analysis of Sanfilippo syndrome type A (MPS IIIA): identification of 13 novel mutations. | Beesley CE | Journal of medical genetics | 2000 | PMID: 11182930 |
Heparan N-sulfatase gene: two novel mutations and transient expression of 15 defects. | Esposito S | Biochimica et biophysica acta | 2000 | PMID: 10727844 |
Mutation 1091delC is highly prevalent in Spanish Sanfilippo syndrome type A patients. | Montfort M | Human mutation | 1998 | PMID: 9744479 |
Identification of molecular defects in Italian Sanfilippo A patients including 13 novel mutations. | Di Natale P | Human mutation | 1998 | PMID: 9554748 |
Identification of 16 sulfamidase gene mutations including the common R74C in patients with mucopolysaccharidosis type IIIA (Sanfilippo A). | Bunge S | Human mutation | 1997 | PMID: 9401012 |
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Text-mined citations for rs1479831530 ...
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.