ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.892T>C (p.Ser298Pro) (rs138504221)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078357 SCV000232027 pathogenic not provided 2013-01-23 criteria provided, single submitter clinical testing
GeneDx RCV000078357 SCV000321948 pathogenic not provided 2021-05-05 criteria provided, single submitter clinical testing Published functional studies demonstrate an effect on folding and stability of the sulfamidase enzyme, resulting in significantly reduced enzymatic activity (Muschol et al., 2011) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function This variant is associated with the following publications: (PMID: 31980526, 31536183, 32581362, 31718697, 29023963, 28451919, 24524415, 21204211, 24271936, 21061399, 15146460, 22976768, 24816101, 26787381, 18407553, 25807448, 9401012, 21671382)
Illumina Clinical Services Laboratory,Illumina RCV000023412 SCV000407355 pathogenic Mucopolysaccharidosis, MPS-III-A 2017-04-28 criteria provided, single submitter clinical testing The SGSH c.892T>C (p.Ser298Pro) variant has been reported in four studies and is found in a total of 51 individuals with mucopolysaccharidosis, type III including four in a homozygous state, 45 in a compound heterozygous state, and two in a heterozygous state in whom a second variant was not identified (Bunge et al. 1997; Meyer et al. 2008; Valstar et al. 2010; Shapiro et al. 2016). Individuals carrying the p.Ser298Pro variant demonstrate a milder phenotype (Meyer et al. 2008; Valstar et al. 2010). The p.Ser298Pro variant was absent from 100 controls but is reported at a frequency of 0.00017 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in BHK cells transfected with the p.Ser298Pro variant demonstrated the variant results in reduced protein stability compared to wild type as well as low residual sulfamidase activity (Muschol et al. 2011). Based on the collective evidence, the p.Ser298Pro variant is classified as pathogenic for mucopolysaccharidosis, type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000326423 SCV000695961 pathogenic Sanfilippo syndrome 2017-08-02 criteria provided, single submitter clinical testing Variant summary: The SGSH c.892T>C (p.Ser298Pro) variant involves the alteration of a conserved nucleotide that lies within the Alkaline-phosphatase-like, core domain, Sulfatase, N-terminal domain, and Alkaline phosphatase-like, alpha/beta/alpha domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies found no to minimal (2.3% of wild-type) heparin-N sulfatase activity associated with this variant (Pollard_JIMD_2013, Muschol_AJMG_2011). This variant was found in the large control database ExAC and in the literature at a frequency of 0.0000917 (11/120004 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic SGSH variant (0.0032275). The variant has been found in numerous MPS IIIA patients, in compound heterozygotes as well as homozygotes, and was reported as being associated with a clinically mild phenotype (Valstar_Mutat_Annals of Neurology_2010, Meyer_HM_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000023412 SCV000745248 pathogenic Mucopolysaccharidosis, MPS-III-A 2015-09-21 criteria provided, single submitter clinical testing
Invitae RCV000023412 SCV000951275 pathogenic Mucopolysaccharidosis, MPS-III-A 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 298 of the SGSH protein (p.Ser298Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. This variant is present in population databases (rs138504221, ExAC 0.02%). This variant has been observed to be homozygous or in combination with another pathogenic variant in SGSH in several individuals affected with mucopolysaccharidosis type IIIA (PMID: 9401012, 18407553, 21671382, 22976768, 29023963). ClinVar contains an entry for this variant (Variation ID: 30459). Experimental studies have shown that this missense change reduces SGSH enzymatic activity in vitro (PMID: 21671382). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000023412 SCV001163431 pathogenic Mucopolysaccharidosis, MPS-III-A criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078357 SCV001247661 pathogenic not provided 2018-01-01 criteria provided, single submitter clinical testing
Undiagnosed Diseases Network,NIH RCV000023412 SCV001432757 pathogenic Mucopolysaccharidosis, MPS-III-A 2020-04-30 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing PMIDs 21671382, 29023963, 9401012, 24816101, 25807448.
Genomics England Pilot Project,Genomics England RCV000023412 SCV001760412 pathogenic Mucopolysaccharidosis, MPS-III-A criteria provided, single submitter clinical testing
OMIM RCV000023412 SCV000044703 pathogenic Mucopolysaccharidosis, MPS-III-A 2010-12-01 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000023412 SCV000733740 pathogenic Mucopolysaccharidosis, MPS-III-A no assertion criteria provided clinical testing
Counsyl RCV000023412 SCV001132484 pathogenic Mucopolysaccharidosis, MPS-III-A 2016-12-10 no assertion criteria provided clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003995 SCV001162039 pathogenic Global developmental delay; Diarrhea; Nystagmus; Retinal dystrophy; Severe visual impairment; Developmental regression; Gastrointestinal dysmotility no assertion criteria provided research
GeneReviews RCV001030818 SCV001194307 pathogenic Mucopolysaccharidosis 2019-09-04 no assertion criteria provided literature only
Natera, Inc. RCV000023412 SCV001463877 pathogenic Mucopolysaccharidosis, MPS-III-A 2020-09-16 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000078357 SCV001799065 pathogenic not provided no assertion criteria provided clinical testing

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