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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001132284	Counsyl	no assertion criteria provided	Uncertain significance (Feb 13, 2018)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9554748, 10727844, 24816101
SCV003442425	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 19, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10727844, 28492532
SCV003934347	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (May 26, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9554748, 10727844, 11903343 Citation Link,
SCV004201121	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 27, 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	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

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

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

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

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

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

#	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 Baylor Genetics, SCV004201121.2

#	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 8, 2024

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