NM_000199.5(SGSH):c.449G>A (p.Arg150Gln) AND Mucopolysaccharidosis, MPS-III-A

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Jan 18, 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:: RCV000005420.21

Allele description [Variation Report for NM_000199.5(SGSH):c.449G>A (p.Arg150Gln)]

NM_000199.5(SGSH):c.449G>A (p.Arg150Gln)

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.449G>A (p.Arg150Gln)

HGVS:

NC_000017.11:g.80214672C>T
NG_008229.1:g.10729G>A
NM_000199.5:c.449G>AMANE SELECT
NM_001352921.3:c.449G>A
NM_001352922.2:c.449G>A
NP_000190.1:p.Arg150Gln
NP_001339850.1:p.Arg150Gln
NP_001339851.1:p.Arg150Gln
NC_000017.10:g.78188471C>T
NM_000199.3:c.449G>A
NR_148201.2:n.363G>A
P51688:p.Arg150Gln

Protein change:

R150Q; ARG150GLN

Links:

UniProtKB: P51688#VAR_007402; OMIM: 605270.0005; dbSNP: rs104894638

NCBI 1000 Genomes Browser:

rs104894638

Molecular consequence:

NM_000199.5:c.449G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001352921.3:c.449G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001352922.2:c.449G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_148201.2:n.363G>A - 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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PfRrp6-DD-1B_R_rep2_RNA-seq
PfRrp6-DD-1B_R_rep2_RNA-seq

biosample
polyamine-modulated factor 1-binding protein 1 isoform X3 [Homo sapiens]
polyamine-modulated factor 1-binding protein 1 isoform X3 [Homo sapiens]
gi|2217307723|ref|XP_047290690.1|

Protein
Mus musculus solute carrier family 16 (monocarboxylic acid transporters), member...
Mus musculus solute carrier family 16 (monocarboxylic acid transporters), member 5 (Slc16a5), transcript variant 2, mRNA
gi|1327848675|ref|NM_001359606.1|

Nucleotide
olfactory receptor 6K3-like [Mus caroli]
olfactory receptor 6K3-like [Mus caroli]
gi|1195670839|ref|XP_021028147.1|

Protein
SRX9099450 (1)
SRA

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000025602	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 1998)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 9744479, 9554748
SCV000754682	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 18, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 9401012, 9554748, 9744479, 11343308, 21061399, 10727844, 11182930, 21204211, 28492532
SCV000798966	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Apr 2, 2018)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11343308, 9401012, 21061399, 10727844, 9554748 Citation Link,
SCV000920207	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 4, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21204211, 21061399, 9401012, 11668611, 10727844, 9554748 Citation Link,
SCV002045504	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002095140	Natera, Inc.	no assertion criteria provided	Pathogenic (Aug 17, 2020)	germline	clinical testing
SCV002778765	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 6, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004201124	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 19, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	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
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation 1091delC is highly prevalent in Spanish Sanfilippo syndrome type A patients.

Montfort M, Vilageliu L, Garcia-Giralt N, Guidi S, Coll MJ, Chabás A, Grinberg D.

Hum Mutat. 1998;12(4):274-9.

PubMed [citation]

PMID:: 9744479

Mutational analysis of Sanfilippo syndrome type A (MPS IIIA): identification of 13 novel mutations.

Beesley CE, Young EP, Vellodi A, Winchester BG.

J Med Genet. 2000 Sep;37(9):704-7. No abstract available.

PubMed [citation]

PMID:: 11182930
PMCID:: PMC1734705

See all PubMed Citations (11)

Details of each submission

From OMIM, SCV000025602.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a Spanish patient with mucopolysaccharidosis type IIIA (MPS3A; 252900), Montfort et al. (1998) found an arg150-to-glu (R150Q) mutation in exon 4 of the SGSH gene. The same mutation had previously been identified by Di Natale et al. (1998).

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000754682.7

#	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 glutamine, which is neutral and polar, at codon 150 of the SGSH protein (p.Arg150Gln). This variant is present in population databases (rs104894638, gnomAD 0.005%). This missense change has been observed in individuals with mucopolysaccharidosis type III (PMID: 9401012, 9554748, 9744479, 11343308, 21061399, 21204211). ClinVar contains an entry for this variant (Variation ID: 5113). 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 80%. Experimental studies have shown that this missense change affects SGSH function (PMID: 10727844). This variant disrupts the p.Arg150 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been observed in individuals with SGSH-related conditions (PMID: 11182930, 21204211), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as 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 Counsyl, SCV000798966.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000920207.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: SGSH c.449G>A (p.Arg150Gln) results in a conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 276994 control chromosomes (gnomAD and publication data). c.449G>A has been reported in the literature as a homozygous and compound heterozygous allele in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (Bunge 1997, Di Natale 1998, Heron 2010, Valstar 2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on enzyme activity, showing that the variant results in <10% of normal activity (Esposito 2000). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as 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 Genome-Nilou Lab, SCV002045504.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002095140.1

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

#	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 Fulgent Genetics, Fulgent Genetics, SCV002778765.1

#	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, SCV004201124.2

#	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: Oct 13, 2024

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