NM_000199.5(SGSH):c.733C>T (p.Arg245Cys) AND Mucopolysaccharidosis, MPS-III-A

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: Jan 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001783741.11

Allele description [Variation Report for NM_000199.5(SGSH):c.733C>T (p.Arg245Cys)]

NM_000199.5(SGSH):c.733C>T (p.Arg245Cys)

Gene:

SGSH:N-sulfoglucosamine sulfohydrolase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000199.5(SGSH):c.733C>T (p.Arg245Cys)

HGVS:

NC_000017.11:g.80213816G>A
NG_008229.1:g.11585C>T
NM_000199.5:c.733C>TMANE SELECT
NM_001352921.3:c.733C>T
NM_001352922.2:c.733C>T
NP_000190.1:p.Arg245Cys
NP_001339850.1:p.Arg245Cys
NP_001339851.1:p.Arg245Cys
NC_000017.10:g.78187615G>A
NM_000199.4:c.733C>T
NR_148201.2:n.647C>T

Protein change:

R245C

Links:

dbSNP: rs1455698449

NCBI 1000 Genomes Browser:

rs1455698449

Molecular consequence:

NM_000199.5:c.733C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352921.3:c.733C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352922.2:c.733C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_148201.2:n.647C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Mucopolysaccharidosis, MPS-III-A (MPS3A)
Synonyms:: SULFAMIDASE DEFICIENCY; Mucopoly-saccharidosis type 3A; Sanfilippo syndrome A; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009655; MedGen: C0086647; Orphanet: 581; Orphanet: 79269; OMIM: 252900

Recent activity

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RecName: Full=Granulocyte colony-stimulating factor receptor; Short=G-CSF recept...
RecName: Full=Granulocyte colony-stimulating factor receptor; Short=G-CSF receptor; Short=G-CSF-R; AltName: CD_antigen=CD114; Flags: Precursor
gi|341940404|sp|P40223.2|CSF3R_MOUS

Protein
Homo sapiens Zn regulated GTPase metalloprotein activator 1C (ZNG1C), transcript...
Homo sapiens Zn regulated GTPase metalloprotein activator 1C (ZNG1C), transcript variant 1, mRNA
gi|1802776450|ref|NM_201453.4|

Nucleotide
Homo sapiens cDNA clone IMAGE:4838661
Homo sapiens cDNA clone IMAGE:4838661
gi|21618628|gb|BC031942.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002272520	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 29, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 34991944, 9158154, 9700599, 10601282, 15146460, 21061399, 22976768, 26331342, 28492532
SCV002556945	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 27, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002811623	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 6, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004201080	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 29, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

An observational, prospective, multicenter, natural history study of patients with mucopolysaccharidosis type IIIA.

Wijburg FA, Aiach K, Chakrapani A, Eisengart JB, Giugliani R, Héron B, Muschol N, O'Neill C, Olivier S, Parker S.

Mol Genet Metab. 2022 Feb;135(2):133-142. doi: 10.1016/j.ymgme.2021.12.002. Epub 2021 Dec 10.

PubMed [citation]

PMID:: 34991944

Molecular defects in Sanfilippo syndrome type A.

Blanch L, Weber B, Guo XH, Scott HS, Hopwood JJ.

Hum Mol Genet. 1997 May;6(5):787-91.

PubMed [citation]

PMID:: 9158154

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002272520.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 245 of the SGSH protein (p.Arg245Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIA (PMID: 34991944). ClinVar contains an entry for this variant (Variation ID: 1325064). 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%. This variant disrupts the p.Arg245 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9158154, 9700599, 10601282, 15146460, 21061399, 22976768, 26331342). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV002556945.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PM1, PM2, PM5

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002811623.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004201080.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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