This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 74 of the SGSH protein (p.Arg74Cys). This variant is present in population databases (rs104894636, gnomAD 0.04%). This missense change has been observed in individuals with MPS type IIIA (PMID: 9285796, 9401012, 22976768, 28844463). ClinVar contains an entry for this variant (Variation ID: 5108). 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: 10601282, 15146460). This variant disrupts the p.Arg74 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been observed in individuals with SGSH-related conditions (PMID: 9401012, 15542396), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
Help
- Interpretation:
-
Pathogenic/Likely pathogenic
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 22
- First in ClinVar:
- Jul 16, 2015
- Most recent Submission:
- Nov 20, 2023
- Last evaluated:
- Nov 1, 2022
- Accession:
- VCV000005108.54
- Variation ID:
- 5108
- Description:
- single nucleotide variant
Help
NM_000199.5(SGSH):c.220C>T (p.Arg74Cys)
- Allele ID
- 20147
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 17q25.3
- Genomic location
- 17: 80217061 (GRCh38) GRCh38 UCSC
- 17: 78190860 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000199.5:c.220C>T MANE Select NP_000190.1:p.Arg74Cys missense NM_001352921.3:c.220C>T NP_001339850.1:p.Arg74Cys missense NM_001352922.2:c.220C>T NP_001339851.1:p.Arg74Cys missense NR_148201.2:n.240C>T non-coding transcript variant NC_000017.11:g.80217061G>A NC_000017.10:g.78190860G>A NG_008229.1:g.8340C>T P51688:p.Arg74Cys - Protein change
- R74C
- Other names
- -
- Canonical SPDI
- NC_000017.11:80217060:G:A
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- Exome Aggregation Consortium (ExAC) 0.00023
- Trans-Omics for Precision Medicine (TOPMed) 0.00010
- The Genome Aggregation Database (gnomAD) 0.00051
- The Genome Aggregation Database (gnomAD), exomes 0.00015
- Trans-Omics for Precision Medicine (TOPMed) 0.00017
- The Genome Aggregation Database (gnomAD) 0.00021
- Links
- ClinGen: CA117258
- UniProtKB: P51688#VAR_007391
- OMIM: 605270.0002
- dbSNP: rs104894636
- VarSome
Help
Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Pathogenic/Likely pathogenic | 16 | criteria provided, multiple submitters, no conflicts | Nov 1, 2022 | RCV000005415.46 | |
| Pathogenic | 4 | criteria provided, multiple submitters, no conflicts | Sep 1, 2022 | RCV000078354.32 | |
| Likely pathogenic | 1 | criteria provided, single submitter | Jan 1, 2017 | RCV000626628.10 | |
| not provided | 1 | no assertion provided | - | RCV001030813.10 |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Pathogenic
(Jun 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: yes
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000590925.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
Ethnicity/Population group: Persian
Geographic origin: Iran
|
|
|
Pathogenic
(Sep 21, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745252.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
|
|
|
Pathogenic
(Sep 02, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000227052.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 8
Zygosity: 8 Single Heterozygote
Sex: mixed
|
|
|
Pathogenic
(Feb 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002813133.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Nov 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000820679.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 74 of the SGSH protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 74 of the SGSH protein (p.Arg74Cys). This variant is present in population databases (rs104894636, gnomAD 0.04%). This missense change has been observed in individuals with MPS type IIIA (PMID: 9285796, 9401012, 22976768, 28844463). ClinVar contains an entry for this variant (Variation ID: 5108). 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: 10601282, 15146460). This variant disrupts the p.Arg74 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been observed in individuals with SGSH-related conditions (PMID: 9401012, 15542396), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321945.8
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate very low sulfamidase production compared to wild-type (Perkins et al., 1999).; In silico analysis supports that this missense variant has a … (more)
Published functional studies demonstrate very low sulfamidase production compared to wild-type (Perkins et al., 1999).; 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: 18407553, 24816101, 11668611, 21061399, 31236806, 28963436, 30809705, 30548430, 10601282, 18392742, 15146460, 11793481, 22976768, 26787381, 21671382, 29023963, 28844463, 9285796, 31718697, 31980526, 32036093, 34349725, 34426522, 31589614, 33726816) (less)
|
|
|
Pathogenic
(Oct 09, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
germline
|
PerkinElmer Genomics
Accession: SCV002021245.2
First in ClinVar: Nov 29, 2021 Last updated: Mar 11, 2023 |
|
|
|
Likely pathogenic
(Jan 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000747329.1
First in ClinVar: May 12, 2018 Last updated: May 12, 2018 |
|
|
|
Pathogenic
(Jan 19, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
paternal
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000782576.1
First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018 |
|
|
|
Likely pathogenic
(Jan 01, 2019)
|
criteria provided, single submitter
Method: literature only
|
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova
Accession: SCV000929892.1
First in ClinVar: Jul 31, 2019 Last updated: Jul 31, 2019 |
Comment:
PS3: Low/absent in vivo enzymatic activity in homozygote. PS3: Low in vitro enzymatic activity. PM2: Very low frequency in GnomAD
|
|
|
Pathogenic
(Dec 26, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001194099.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000199.3(SGSH):c.220C>T(R74C) is classified as pathogenic in the context of mucopolysaccharidosis type IIIA. Sources cited for classification include the following: PMID 9401012, 15146460, 11182930, 18407553, 24314109, … (more)
NM_000199.3(SGSH):c.220C>T(R74C) is classified as pathogenic in the context of mucopolysaccharidosis type IIIA. Sources cited for classification include the following: PMID 9401012, 15146460, 11182930, 18407553, 24314109, 21061399 and 11182930. Classification of NM_000199.3(SGSH):c.220C>T(R74C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
|
Pathogenic
(Sep 25, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366179.2
First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3,PP4.
|
|
|
Pathogenic
(Mar 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV001548177.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Zygosity: 1 Compound Heterozygote
Family history: no
Secondary finding: no
|
|
|
Pathogenic
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002045508.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
|
|
|
Pathogenic
(Jun 16, 2011)
|
criteria provided, single submitter
Method: clinical testing
|
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV003843893.1
First in ClinVar: Apr 23, 2023 Last updated: Apr 23, 2023 |
Comment:
A Heterozygous missense variation in exon 2 of the SGSH gene that results in the amino acid substitution of Cystine for Arginine at codon 74 … (more)
A Heterozygous missense variation in exon 2 of the SGSH gene that results in the amino acid substitution of Cystine for Arginine at codon 74 was detected. The observed variant c.220C>T (p.Arg74Cys) has not been reported in the 1000 genomes and has a MAF of 0.02% in gnomAD databases. The in silico prediction of the variant are possibly damaging by LRT, SIFT and MutationTaster. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. (less)
Zygosity: 1 Compound Heterozygote
Age: 0-9 years
Sex: male
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
|
|
|
Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247663.17
First in ClinVar: May 12, 2020 Last updated: Nov 20, 2023 |
Number of individuals with the variant: 8
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001453824.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(Jan 01, 1997)
|
no assertion criteria provided
Method: literature only
|
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000025597.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 16, 2015 |
Comment on evidence:
Bunge et al. (1997) found that the missense mutation arg74-to-cys (R74C), which alters an evolutionarily conserved amino acid in the active site of the sulfamidase … (more)
Bunge et al. (1997) found that the missense mutation arg74-to-cys (R74C), which alters an evolutionarily conserved amino acid in the active site of the sulfamidase enzyme, was present in 56% of SGSH alleles of 16 Polish patients with mucopolysaccharidosis type IIIA (MPS3A; 252900), whereas it was less frequent (21% of disease alleles) among German patients. The R245H mutation (605270.0001) represented 35% of disease alleles in German patients, but only 3% in Polish patients. Because the combined frequency of the common mutations R74C and R245H in German and Polish populations exceeded 55%, Bunge et al. (1997) suggested that screenings for these 2 mutations would assist molecular genetic diagnosis of MPS IIIA and allow heterozygote testing in these populations. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733744.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760415.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002037524.1 First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
|
|
|
not provided
(-)
|
no assertion provided
Method: literature only
|
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV001194302.2
First in ClinVar: Apr 06, 2020 Last updated: Oct 01, 2022 |
|
Functional evidence
Help| 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 this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mucopolysaccharidosis Type III. | Adam MP | - | 2019 | PMID: 31536183 |
| Molecular diagnosis of patients affected by mucopolysaccharidosis: a multicenter study. | Zanetti A | European journal of pediatrics | 2019 | PMID: 30809705 |
| Clinical, biochemical and molecular features of Iranian families with mucopolysaccharidosis: A case series. | Yassaee VR | Clinica chimica acta; international journal of clinical chemistry | 2017 | PMID: 28844463 |
| Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. | Nykamp K | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28492532 |
| Natural history of Sanfilippo syndrome in Spain. | Delgadillo V | Orphanet journal of rare diseases | 2013 | PMID: 24314109 |
| 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 mutation p.Ser298Pro in the sulphamidase gene (SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis type IIIA (Sanfilippo A syndrome). | Meyer A | Human mutation | 2008 | PMID: 18407553 |
| 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 |
| Mutational analysis of Sanfilippo syndrome type A (MPS IIIA): identification of 13 novel mutations. | Beesley CE | Journal of medical genetics | 2000 | PMID: 11182930 |
| Expression and characterization of wild type and mutant recombinant human sulfamidase. Implications for Sanfilippo (Mucopolysaccharidosis IIIA) syndrome. | Perkins KJ | The Journal of biological chemistry | 1999 | PMID: 10601282 |
| 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 |
| Novel mutations in Sanfilippo A syndrome: implications for enzyme function. | Weber B | Human molecular genetics | 1997 | PMID: 9285796 |
| http://biopolymers.org.ua/pdf/30/5/388/biopolym.cell-2014-30-5-388-en.pdf | - | - | - | - |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SGSH | - | - | - | - |
Text-mined citations for rs104894636...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Dec 09, 2023