ClinVar Genomic variation as it relates to human health
NM_000199.5(SGSH):c.1297C>T (p.Arg433Trp)
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_000199.5(SGSH):c.1297C>T (p.Arg433Trp)
Variation ID: 551014 Accession: VCV000551014.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80210664 (GRCh38) [ NCBI UCSC ] 17: 78184463 (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 Aug 5, 2018 Feb 14, 2024 Dec 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000199.5:c.1297C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000190.1:p.Arg433Trp missense NM_001352921.3:c.*384C>T 3 prime UTR NM_001352922.2:c.*347C>T 3 prime UTR NR_148201.2:n.1211C>T non-coding transcript variant NC_000017.11:g.80210664G>A NC_000017.10:g.78184463G>A NG_008229.1:g.14737C>T NG_032778.1:g.45673G>A LRG_1330:g.45673G>A - Protein change
- R433W
- Other names
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- Canonical SPDI
- NC_000017.11:80210663: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 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
- 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
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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SGSH | - | - |
GRCh38 GRCh38 GRCh37 |
991 | 1471 |
Conditions - Germline
Condition
Help
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
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
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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/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Dec 11, 2023 | RCV000665964.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 16, 2023 | RCV002293469.3 |
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
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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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Likely pathogenic
(Mar 17, 2017)
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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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Counsyl
Accession: SCV000790185.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(Jul 05, 2019)
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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: SCV001361816.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: SGSH c.1297C>T (p.Arg433Trp) results in a non-conservative amino acid change located in a domain of unknown function, DUF4976 (IPR032506) of the encoded protein … (more)
Variant summary: SGSH c.1297C>T (p.Arg433Trp) results in a non-conservative amino acid change located in a domain of unknown function, DUF4976 (IPR032506) 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 2e-05 in 250408 control chromosomes (gnomAD). The variant, c.1297C>T, has been reported in the literature in homozygosity or in compound heterozygous state in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (e.g. Beesley_2000, Chabas_2001, Heron_2011, Pollard_2013). These data indicate that the variant is very likely to be associated with disease. Publications reported no significant sulfamidase activity in fibroblasts from a homozygous patient (Montfort_2004), and in transiently transfected mammalian cells (Muschol_2004). Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic (1x) and pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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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: SCV002045483.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Likely pathogenic
(Aug 17, 2021)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893480.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Jun 16, 2023)
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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: SCV002586588.3
First in ClinVar: Oct 29, 2022 Last updated: Jun 24, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: no significant sulfamidase activity compared to wild-type (Montfort et al., 2004); Not observed at significant frequency in large … (more)
Published functional studies demonstrate a damaging effect: no significant sulfamidase activity compared to wild-type (Montfort et al., 2004); Not observed at 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: 24816101, 25807448, 15542396, 11182930, 29023963, 34991944) (less)
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Pathogenic
(Jul 18, 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:
unknown
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Baylor Genetics
Accession: SCV004201112.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 11, 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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Invitae
Accession: SCV000957485.6
First in ClinVar: Aug 13, 2019 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 433 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 433 of the SGSH protein (p.Arg433Trp). This variant is present in population databases (rs777267343, gnomAD 0.009%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIB (PMID: 11182930, 15542396, 29023963). ClinVar contains an entry for this variant (Variation ID: 551014). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SGSH protein function. Experimental studies have shown that this missense change affects SGSH function (PMID: 15542396). For these reasons, this variant has been classified as Pathogenic. (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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Prediction of phenotypic severity in mucopolysaccharidosis type IIIA. | Knottnerus SJG | Annals of neurology | 2017 | PMID: 29023963 |
Molecular characterization of 355 mucopolysaccharidosis patients reveals 104 novel mutations. | Pollard LM | Journal of inherited metabolic disease | 2013 | PMID: 22976768 |
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 |
Expression and functional characterization of human mutant sulfamidase in insect cells. | Montfort M | Molecular genetics and metabolism | 2004 | PMID: 15542396 |
Transport, enzymatic activity, and stability of mutant sulfamidase (SGSH) identified in patients with mucopolysaccharidosis type III A. | Muschol N | Human mutation | 2004 | PMID: 15146460 |
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 |
Text-mined citations for rs777267343 ...
HelpRecord last updated Feb 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.