ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000023412 SCV000745248 pathogenic Mucopolysaccharidosis, MPS-III-A 2015-09-21 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000023412 SCV000733740 pathogenic Mucopolysaccharidosis, MPS-III-A no assertion criteria provided clinical testing
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 2018-11-28 criteria provided, single submitter clinical testing The S298P variant in the SGSH gene has been reported previously opposite of a second SGSH variant and in the homozygous state, in multiple individual with MPS IIIA, who had a later age of onset and slower progression of symptoms as compared to other individuals with MPS IIIA who harbor other variants (Bunge et al., 1997; Meyer et al., 2008; Muschol et al., 2011; Shapiro et al., 2016). The S298P variant is observed in 29/126414 (0.0229%) alleles from individuals of non-Finnish European background in large population cohorts, with no homozygotes observed (Lek et al., 2016). The S298P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies demonstrate that S298P effects the folding and stability of the sulfamidase enzyme, resulting in significantly reduced enzymatic activity (Muschol et al., 2011). We interpret S298P as a pathogenic variant.
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.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000023412 SCV000951275 pathogenic Mucopolysaccharidosis, MPS-III-A 2018-11-21 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.
OMIM RCV000023412 SCV000044703 pathogenic Mucopolysaccharidosis, MPS-III-A 2010-12-01 no assertion criteria provided literature only

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