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NM_000199.5(SGSH):c.130G>A (p.Ala44Thr) AND Mucopolysaccharidosis, MPS-III-A

Germline classification:
Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:
Feb 27, 2024
Review status:
criteria provided, conflicting classifications
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:
RCV000984216.7

Allele description [Variation Report for NM_000199.5(SGSH):c.130G>A (p.Ala44Thr)]

NM_000199.5(SGSH):c.130G>A (p.Ala44Thr)

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.130G>A (p.Ala44Thr)
HGVS:
  • NC_000017.11:g.80217151C>T
  • NG_008229.1:g.8250G>A
  • NM_000199.5:c.130G>AMANE SELECT
  • NM_001352921.3:c.130G>A
  • NM_001352922.2:c.130G>A
  • NP_000190.1:p.Ala44Thr
  • NP_001339850.1:p.Ala44Thr
  • NP_001339851.1:p.Ala44Thr
  • NC_000017.10:g.78190950C>T
  • NM_000199.3:c.130G>A
  • NR_148201.2:n.150G>A
Protein change:
A44T
Links:
dbSNP: rs1057521146
NCBI 1000 Genomes Browser:
rs1057521146
Molecular consequence:
  • NM_000199.5:c.130G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001352921.3:c.130G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001352922.2:c.130G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148201.2:n.150G>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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001132284Counsyl
no assertion criteria provided
Uncertain significance
(Feb 13, 2018)
unknownclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV003442425Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Aug 19, 2022)
germlineclinical testing

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

SCV003934347Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely pathogenic
(May 26, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV004201121Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Feb 27, 2024)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

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

Structure of sulfamidase provides insight into the molecular pathology of mucopolysaccharidosis IIIA.

Sidhu NS, Schreiber K, Pröpper K, Becker S, Usón I, Sheldrick GM, Gärtner J, Krätzner R, Steinfeld R.

Acta Crystallogr D Biol Crystallogr. 2014 May;70(Pt 5):1321-35. doi: 10.1107/S1399004714002739. Epub 2014 Apr 30.

PubMed [citation]
PMID:
24816101
PMCID:
PMC4014121

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818
See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV001132284.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003442425.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 44 of the SGSH protein (p.Ala44Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 10727844). ClinVar contains an entry for this variant (Variation ID: 381685). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects SGSH function (PMID: 10727844). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003934347.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: SGSH c.130G>A (p.Ala44Thr) results in a non-conservative amino acid change located in the sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 225592 control chromosomes (gnomAD). c.130G>A has been reported in the literature as a compound heterozygous genotype and an uninformative genotype (i.e. zygosity not specified) in at least two individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (e.g. Di Natale_1998, Esposito_2000, Kroepfl_2001). Experimental evidence evaluating an impact on protein function found that the variant resulted an enzyme activity that was indistinguishable from the negative control, at <10% of the WT protein (Esposito_2000). The following publications have been ascertained in the context of this evaluation (PMID: 9554748, 10727844, 11903343). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

From Baylor Genetics, SCV004201121.2

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

Last Updated: Oct 8, 2024