ClinVar Genomic variation as it relates to human health
NM_000199.5(SGSH):c.703G>A (p.Asp235Asn)
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
-
NM_000199.5(SGSH):c.703G>A (p.Asp235Asn)
Variation ID: 553004 Accession: VCV000553004.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q25.3 17: 80213846 (GRCh38) [ NCBI UCSC ] 17: 78187645 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 30, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000199.5:c.703G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000190.1:p.Asp235Asn missense NM_001352921.3:c.703G>A NP_001339850.1:p.Asp235Asn missense NM_001352922.2:c.703G>A NP_001339851.1:p.Asp235Asn missense NR_148201.2:n.617G>A non-coding transcript variant NC_000017.11:g.80213846C>T NC_000017.10:g.78187645C>T NG_008229.1:g.11555G>A - Protein change
- D235N
- Other names
- -
- Canonical SPDI
- NC_000017.11:80213845:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00008
- Links
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 | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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
Help
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. |
|||
SGSH | - | - |
GRCh38 GRCh38 GRCh37 |
992 | 1474 |
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
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2024 | RCV000668365.12 | |
SGSH-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Oct 13, 2022 | RCV003420182.5 |
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
Help
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. |
|
---|---|---|---|---|---|
Pathogenic
(Oct 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000963681.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 235 of the SGSH protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 235 of the SGSH protein (p.Asp235Asn). This variant is present in population databases (rs753472891, gnomAD 0.02%). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 11182930, 12000360, 19099774; Invitae). ClinVar contains an entry for this variant (Variation ID: 553004). 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. Experimental studies have shown that this missense change affects SGSH function (PMID: 12000360). This variant disrupts the p.Asp235 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been observed in individuals with SGSH-related conditions (PMID: 9401012), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Likely pathogenic
(Jul 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000792951.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
Likely pathogenic
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002045496.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
|
|
Pathogenic
(May 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002547900.1
First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
Variant summary: SGSH c.703G>A (p.Asp235Asn) results in a conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Four … (more)
Variant summary: SGSH c.703G>A (p.Asp235Asn) results in a conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 237402 control chromosomes (gnomAD). c.703G>A has been reported in the literature in compound heterozygous individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (Beesley_2000, Lee-Chen_2002, Heron_2011). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon (Asp235Val) has been reported in affected individuals, suggesting this may be an important residue (Beesley_2000). One publication reports that the variant protein has 1.7% N-Sulphatase activity (Lee-Chen_2002). Three ClinVar submitters have assessed the variant since 2014: two classify the variant as likely pathogenic and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Oct 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
SGSH-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004118381.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The SGSH c.703G>A variant is predicted to result in the amino acid substitution p.Asp235Asn. This variant along with a second variant in SGSH was reported … (more)
The SGSH c.703G>A variant is predicted to result in the amino acid substitution p.Asp235Asn. This variant along with a second variant in SGSH was reported in multiple individuals with Sanfilippo syndrome IIIA (also known as Sanfilippo A) (Beesley et al. 2000. PubMed ID: 11182930; Zhang et al. 2008. PubMed ID: 19099774; Lee-Chen et al. 2002. PubMed ID: 12000360; Table S2, Héron et al. 2011. PubMed ID: 21204211; Delgadillo et al. 2013. PubMed ID: 24314109). In addition, a different variant affecting the same amino acid (p.Asp235Val) was reported to be pathogenic for Sanfilippo syndrome A (Bunge et al. 1997. PubMed ID: 9401012). Structure and computational predication studies suggest this variant disrupts enzyme activity (Sidhu et al. 2014. PubMed ID: 24816101; Ugrinov et al. 2015. PubMed ID: 25807448). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-78187645-C-T). This variant is interpreted as pathogenic. (less)
|
|
Likely pathogenic
(Mar 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004201077.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
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 |
---|---|---|---|---|
Natural history of Sanfilippo syndrome in Spain. | Delgadillo V | Orphanet journal of rare diseases | 2013 | PMID: 24314109 |
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 |
[Postnatal and prenatal diagnosis of mucopolysaccharidosis type III (Sanfilippo syndrome)]. | Zhang WM | Zhonghua er ke za zhi = Chinese journal of pediatrics | 2008 | PMID: 19099774 |
Identification and characterization of mutations underlying Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA). | Lee-Chen GJ | Clinical genetics | 2002 | PMID: 12000360 |
Mutational analysis of Sanfilippo syndrome type A (MPS IIIA): identification of 13 novel mutations. | Beesley CE | Journal of medical genetics | 2000 | PMID: 11182930 |
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 |
Text-mined citations for rs753472891 ...
HelpRecord last updated Jun 23, 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.