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

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Aug 29, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000005420.8

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_001352921.2: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_001352921.2: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

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000025602OMIMno assertion criteria providedPathogenic
(Jan 1, 1998)
germlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000754682Invitaecriteria provided, single submitter
Pathogenic
(Aug 29, 2020)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV000798966Counsylcriteria provided, single submitter
Likely pathogenic
(Apr 2, 2018)
unknownclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV000920207Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Oct 4, 2018)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedunknownunknownnot providednot providednot providednot providednot providedclinical 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 (10)

Details of each submission

From OMIM, SCV000025602.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature 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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000754682.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This sequence change replaces arginine with glutamine at codon 150 of the SGSH protein (p.Arg150Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs104894638, ExAC 0.01%). This variant has been reported as homozygous or in combination with another SGSH variant in individuals affected with mucopolysaccharidosis type III (PMID: 9401012, 9554748, 9744479, 21204211, 11343308, 21061399). ClinVar contains an entry for this variant (Variation ID: 5113). Experimental studies have shown that this missense change abrogates SGSH enzyme activity (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 allele has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Counsyl, SCV000798966.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 14, 2021

Support Center