PS3: Low/absent in vivo enzymatic activity in homozygote. PS3: Low in vitro enzymatic activity. PM2: Very low frequency in GnomAD
ClinVar Genomic variation as it relates to human health
NM_000199.5(SGSH):c.220C>T (p.Arg74Cys)
Germline
Classification
Help
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.
(23)
Help
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/Likely pathogenic
23
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000199.5(SGSH):c.220C>T (p.Arg74Cys)
Variation ID: 5108 Accession: VCV000005108.65
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q25.3 17: 80217061 (GRCh38) [ NCBI UCSC ] 17: 78190860 (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 Jul 16, 2015 Oct 20, 2024 Mar 28, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000199.5:c.220C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
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 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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00010
The Genome Aggregation Database (gnomAD), exomes 0.00015
The Genome Aggregation Database (gnomAD) 0.00021
Exome Aggregation Consortium (ExAC) 0.00023
- 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 |
997 | 1479 | |
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 (17) |
criteria provided, multiple submitters, no conflicts
|
Mar 28, 2024 | RCV000005415.52 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 1, 2023 | RCV000078354.41 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jan 1, 2017 | RCV000626628.10 | |
| not provided (1) |
no classification provided
|
- | RCV001030813.10 |
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
(Sep 21, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
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 |
|
|
|
Likely pathogenic
(Jan 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Abnormal circulating carbohydrate concentration
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 |
|
|
|
Likely pathogenic
(Jan 01, 2019)
|
criteria provided, single submitter
Method: literature only
|
Mucopolysaccharidosis, MPS-III-A
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
(Sep 02, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
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
Sex: mixed
|
|
|
Pathogenic
(Dec 26, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
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
|
Mucopolysaccharidosis, MPS-III-A
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
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
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
|
Mucopolysaccharidosis, MPS-III-A
(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)
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
(Oct 09, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021245.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jun 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
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
(Jan 19, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
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 |
|
|
|
Pathogenic
(Mar 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
(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 |
Family history: no
Secondary finding: no
|
|
|
Pathogenic
(Feb 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
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
(Mar 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
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
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000820679.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
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 with a positive predictive value of 95%. 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 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004201087.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Dec 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247663.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
SGSH: PM3:Very Strong, PM2, PM5, PP3, PS3:Supporting
Number of individuals with the variant: 9
|
|
|
Pathogenic
(Jan 01, 1997)
|
no assertion criteria provided
Method: literature only
|
MUCOPOLYSACCHARIDOSIS, TYPE IIIA
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
|
Mucopolysaccharidosis, MPS-III-A
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
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Mucopolysaccharidosis type IIIA
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001453824.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
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
|
not provided
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 classification provided
Method: literature only
|
Mucopolysaccharidosis
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV001194302.2
First in ClinVar: Apr 06, 2020 Last updated: Oct 01, 2022 |
|
|
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Comment:
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, 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.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3,PP4.
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 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.
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 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)
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 (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 with a positive predictive value of 95%. 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.
Comment:
SGSH: PM3:Very Strong, PM2, PM5, PP3, PS3:Supporting
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. |
Comment:
PS3: Low/absent in vivo enzymatic activity in homozygote. PS3: Low in vitro enzymatic activity. PM2: Very low frequency in GnomAD
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, 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.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3,PP4.
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 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.
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 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)
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 (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 with a positive predictive value of 95%. 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.
Comment:
SGSH: PM3:Very Strong, PM2, PM5, PP3, PS3:Supporting
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| 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 | - | - | - | - |
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Text-mined citations for rs104894636 ...
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Record last updated Nov 25, 2024
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