ClinVar Miner

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

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 2021-03-25 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect with reduced protein quantity and activity (Perkins et al., 1999; Montfort et al., 2004); 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: 30809705, 29023963, 21228398, 24816101, 25807448, 10521831, 9158154, 10601282, 9554748, 15542396, 31980526)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000005418 SCV000745253 pathogenic Mucopolysaccharidosis, MPS-III-A 2015-09-21 criteria provided, single submitter clinical testing
Invitae RCV000005418 SCV000831148 pathogenic Mucopolysaccharidosis, MPS-III-A 2020-10-20 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.
Myriad Women's Health, Inc. RCV000005418 SCV001193883 pathogenic Mucopolysaccharidosis, MPS-III-A 2019-12-24 criteria provided, single submitter clinical testing NM_000199.3(SGSH):c.197C>G(S66W) is classified as pathogenic in the context of mucopolysaccharidosis type IIIA. Sources cited for classification include the following: PMID 10601282, 15542396, 9158154, 11182930 and 9554748. Classification of NM_000199.3(SGSH):c.197C>G(S66W) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Undiagnosed Diseases Network,NIH RCV000005418 SCV001432758 pathogenic Mucopolysaccharidosis, MPS-III-A 2020-04-30 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing PMIDs 10601282, 9554748, 29023963, 21228398, 9158154, 24816101, 15542396, 10521831, 25807448.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000005418 SCV001448842 pathogenic Mucopolysaccharidosis, MPS-III-A 2019-11-18 criteria provided, single submitter clinical testing
OMIM RCV000005418 SCV000025600 pathogenic Mucopolysaccharidosis, MPS-III-A 1999-10-01 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000005418 SCV000733745 pathogenic Mucopolysaccharidosis, MPS-III-A no assertion criteria provided clinical testing
GeneReviews RCV001030815 SCV001194304 pathogenic Mucopolysaccharidosis 2019-09-04 no assertion criteria provided literature only
Natera, Inc. RCV000005418 SCV001453825 pathogenic Mucopolysaccharidosis, MPS-III-A 2020-09-16 no assertion criteria provided clinical testing

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