ClinVar Genomic variation as it relates to human health
NM_000199.5(SGSH):c.1167C>A (p.Asn389Lys)
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.1167C>A (p.Asn389Lys)
Variation ID: 550465 Accession: VCV000550465.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80210794 (GRCh38) [ NCBI UCSC ] 17: 78184593 (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 Jun 17, 2024 Mar 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000199.5:c.1167C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000190.1:p.Asn389Lys missense NM_001352921.3:c.*254C>A 3 prime UTR NM_001352922.2:c.*217C>A 3 prime UTR NR_148201.2:n.1081C>A non-coding transcript variant NC_000017.11:g.80210794G>T NC_000017.10:g.78184593G>T NG_008229.1:g.14607C>A NG_032778.1:g.45803G>T LRG_1330:g.45803G>T - Protein change
- N389K
- Other names
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- Canonical SPDI
- NC_000017.11:80210793:G: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.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- 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 |
987 | 1465 |
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
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 (5) |
criteria provided, multiple submitters, no conflicts
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Mar 27, 2024 | RCV000665218.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 1, 2023 | RCV002275097.12 |
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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Likely pathogenic
(Jan 26, 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: SCV000789296.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(Aug 02, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001339049.3
First in ClinVar: Jun 22, 2020 Last updated: Oct 04, 2023 |
Comment:
Variant summary: SGSH c.1167C>A (p.Asn389Lys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: SGSH c.1167C>A (p.Asn389Lys) results in a non-conservative amino acid change in 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 251050 control chromosomes (gnomAD). c.1167C>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A; e.g. Bunge_1997, Valstar_2010, Wijburg_2022). In addition, the variant has also been reported in heterozygous state in individuals with a clinical phenotype of neuronal ceroid lipofuscinosis (DiFruscio_2015). 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. However, a different missense affecting the same codon (p.Asn389Ser) is classified as pathogenic by our laboratory, indicating that this residue is clinically important. The following publications have been ascertained in the context of this evaluation (PMID: 9401012, 9744479, 11668611, 21061399, 24816101, 26075876, 25807448, 32036093). Four other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 17, 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: SCV001419344.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 389 of the SGSH protein (p.Asn389Lys). … (more)
This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 389 of the SGSH protein (p.Asn389Lys). This variant is present in population databases (rs764057581, gnomAD 0.004%). This missense change has been observed in individuals with mucopolysaccharidosis type III (PMID: 11903343, 21061399, 34991944). ClinVar contains an entry for this variant (Variation ID: 550465). 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. This variant disrupts the p.Asn389 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22976768). 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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Pathogenic
(Nov 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002563446.12
First in ClinVar: Aug 23, 2022 Last updated: Jun 17, 2024 |
Comment:
SGSH: PM3:Very Strong, PM2, PM5, PP4
Number of individuals with the variant: 3
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Pathogenic
(Mar 27, 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: SCV004201090.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Likely pathogenic
(Jun 18, 2020)
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no assertion criteria provided
Method: clinical testing
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Mucopolysaccharidosis type IIIA
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002095117.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 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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An observational, prospective, multicenter, natural history study of patients with mucopolysaccharidosis type IIIA. | Wijburg FA | Molecular genetics and metabolism | 2022 | PMID: 34991944 |
Setup and Validation of a Targeted Next-Generation Sequencing Approach for the Diagnosis of Lysosomal Storage Disorders. | Zanetti A | The Journal of molecular diagnostics : JMD | 2020 | PMID: 32036093 |
Lysoplex: An efficient toolkit to detect DNA sequence variations in the autophagy-lysosomal pathway. | Di Fruscio G | Autophagy | 2015 | PMID: 26075876 |
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 |
Molecular characterization of 355 mucopolysaccharidosis patients reveals 104 novel mutations. | Pollard LM | Journal of inherited metabolic disease | 2013 | PMID: 22976768 |
Mucopolysaccharidosis type IIIA: clinical spectrum and genotype-phenotype correlations. | Valstar MJ | Annals of neurology | 2010 | PMID: 21061399 |
The frequency of common mutations among patients with mucopolysaccharidosis types I, II and IIIA diagnosed in Austria over the last 17 years. | Kroepfl T | Clinical genetics | 2001 | PMID: 11903343 |
Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications. | Yogalingam G | Human mutation | 2001 | PMID: 11668611 |
Mutation 1091delC is highly prevalent in Spanish Sanfilippo syndrome type A patients. | Montfort M | Human mutation | 1998 | PMID: 9744479 |
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 rs764057581 ...
HelpRecord last updated Jun 17, 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.