NM_000199.5(SGSH):c.268G>A (p.Gly90Arg) AND Mucopolysaccharidosis, MPS-III-A

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Nov 15, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000665315.4

Allele description [Variation Report for NM_000199.5(SGSH):c.268G>A (p.Gly90Arg)]

NM_000199.5(SGSH):c.268G>A (p.Gly90Arg)

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.268G>A (p.Gly90Arg)
HGVS:
  • NC_000017.11:g.80215120C>T
  • NG_008229.1:g.10281G>A
  • NM_000199.5:c.268G>AMANE SELECT
  • NM_001352921.2:c.268G>A
  • NM_001352922.2:c.268G>A
  • NP_000190.1:p.Gly90Arg
  • NP_001339850.1:p.Gly90Arg
  • NP_001339851.1:p.Gly90Arg
  • NC_000017.10:g.78188919C>T
  • NM_000199.3:c.268G>A
Protein change:
G90R
Links:
dbSNP: rs774010006
NCBI 1000 Genomes Browser:
rs774010006
Molecular consequence:
  • NM_000199.5:c.268G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001352921.2:c.268G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001352922.2:c.268G>A - missense variant - [Sequence Ontology: SO:0001583]

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000789415Counsylcriteria provided, single submitter
Likely pathogenic
(Feb 1, 2017)
unknownclinical testing

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

Citation Link,

SCV001362833Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Nov 15, 2019)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001372574Invitaecriteria provided, single submitter
Likely pathogenic
(Oct 16, 2019)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Identification of 16 sulfamidase gene mutations including the common R74C in patients with mucopolysaccharidosis type IIIA (Sanfilippo A).

Bunge S, Ince H, Steglich C, Kleijer WJ, Beck M, Zaremba J, van Diggelen OP, Weber B, Hopwood JJ, Gal A.

Hum Mutat. 1997;10(6):479-85.

PubMed [citation]
PMID:
9401012

Combined Hurler and Sanfilippo syndrome in a sibling pair.

Sun A, Hopwood JJ, Thompson J, Cederbaum SD.

Mol Genet Metab. 2011 Jun;103(2):135-7. doi: 10.1016/j.ymgme.2011.02.011. Epub 2011 Feb 22.

PubMed [citation]
PMID:
21393040
See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000789415.1

#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, SCV001362833.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: SGSH c.268G>A (p.Gly90Arg) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248612 control chromosomes (gnomAD). c.268G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A)(Bunge_1997, Sun_2011, Heron_2011, Chistiakov_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites 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

From Invitae, SCV001372574.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces glycine with arginine at codon 90 of the SGSH protein (p.Gly90Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs774010006, ExAC 0.01%). This variant has been observed in combination with another SGSH variant in several individuals affected with mucopolysaccharidosis type III (PMID: 21204211, 21455105, 24875751). ClinVar contains an entry for this variant (Variation ID: 550542). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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

Last Updated: Jun 14, 2021

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