ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.197C>G (p.Ser66Trp) (rs104894637)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000005418 SCV000789936 pathogenic Mucopolysaccharidosis, MPS-III-A 2017-02-27 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000005418 SCV000745253 pathogenic Mucopolysaccharidosis, MPS-III-A 2015-09-21 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000005418 SCV000733745 pathogenic Mucopolysaccharidosis, MPS-III-A no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255782 SCV000227051 pathogenic not provided 2014-09-23 criteria provided, single submitter clinical testing
GeneDx RCV000255782 SCV000321944 pathogenic not provided 2018-10-31 criteria provided, single submitter clinical testing The S66W variant in the SGSH gene has been reported previously in the homozygous and compound heterozygous states in association with mucopolysaccharidosis type IIIA (Blanch et al., 1997; Di Natale et al., 1998; Bell et al., 2011). Functional studies show S66W significantly reduces the protein quantity and activity compared to the wild type, while retaining low levels of activity (Perkins et al., 1999; Montfort et al., 2004). The S66W variant is observed in 23/115,010 (0.02%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The S66W 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret S66W as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000586103 SCV000695958 pathogenic Sanfilippo syndrome 2017-08-02 criteria provided, single submitter clinical testing Variant summary: The SGSH c.197C>G (p.Ser66Trp) variant involves the alteration of a conserved nucleotide located in the Alkaline-phosphatase-like domain of the protein (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 23/251298 control chromosomes at a frequency of 0.0000915, which does not exceed the estimated maximal expected allele frequency of a pathogenic SGSH variant (0.0032275). This variant has been reported in numerous patients both homozygously and compound heterozygously. Functional study showed variant with 10% of WT enzyme activity (Montfort_MGM_2004) In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000005418 SCV000831148 pathogenic Mucopolysaccharidosis, MPS-III-A 2018-10-04 criteria provided, single submitter clinical testing This sequence change replaces serine with tryptophan at codon 66 of the SGSH protein (p.Ser66Trp). The serine residue is highly conserved and there is a large physicochemical difference between serine and tryptophan. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported as homozygous or in combination with another SGSH variant in many individuals affected with mucopolysaccharidosis type IIIA (PMID: 9158154, 9285796, 9554748, 15542396, 22976768), and has been shown to segregate with disease in a family (PMID: 21061399). ClinVar contains an entry for this variant (Variation ID: 5111). Experimental studies have shown that this missense change impairs sulfamidase activity (PMID: 10601282, 15542396). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova RCV000005418 SCV000929891 pathogenic Mucopolysaccharidosis, MPS-III-A 2019-01-01 criteria provided, single submitter literature only PS3: Low in vitro enzymatic activity. PP1: Cosegregation with disease in multiple affected family members (strong evidence). PM2: Very low frequency in GnomAD. PP5: reputable source report variant as pathogenic.
OMIM RCV000005418 SCV000025600 pathogenic Mucopolysaccharidosis, MPS-III-A 1999-10-01 no assertion criteria provided literature only

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