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

gnomAD frequency: 0.00011  dbSNP: rs104894637

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000255782	SCV000227051	pathogenic	not provided	2014-09-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000255782	SCV000321944	pathogenic	not provided	2021-11-04	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: 10521831, 25807448, 24816101, 15542396, 31980526, 9554748, 10601282, 9158154, 21228398, 29023963, 30809705, 34440436, 34349725, 31589614)
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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, 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	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 66 of the SGSH protein (p.Ser66Trp). This variant is present in population databases (rs104894637, gnomAD 0.02%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIA (PMID: 9158154, 9285796, 9554748, 15542396, 21061399, 22976768). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5111). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SGSH protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SGSH function (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 Genetics, 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
Revvity Omics, Revvity	RCV000005418	SCV002021246	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-09-06	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000005418	SCV002045509	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000005418	SCV002556478	pathogenic	Mucopolysaccharidosis, MPS-III-A	2020-03-27	criteria provided, single submitter	clinical testing	PS3, PS4, PP3
MGZ Medical Genetics Center	RCV000005418	SCV002580942	pathogenic	Mucopolysaccharidosis, MPS-III-A	2022-06-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000005418	SCV002809729	pathogenic	Mucopolysaccharidosis, MPS-III-A	2022-05-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512807	SCV003565285	pathogenic	Inborn genetic diseases	2021-02-19	criteria provided, single submitter	clinical testing	The c.197C>G (p.S66W) alteration is located in exon 2 (coding exon 2) of the SGSH gene. This alteration results from a C to G substitution at nucleotide position 197, causing the serine (S) at amino acid position 66 to be replaced by a tryptophan (W). Based on data from the Genome Aggregation Database (gnomAD) database, the SGSH c.197C>G alteration was observed in 0.01% (23/257594) of total alleles studied, with a frequency of 0.02% (23/117902) in the European (non-Finnish) subpopulation. This mutation has been detected as heterozygous, compound heterozygous, and homozygous, in individuals with typical severe presentations of Mucopolysaccaridosis type IIIA (Sanfilippo syndrome type A) (Blanch, 1997; Di Natale, 1998; Valstar, 2010; Ouesleti, 2011; Delgadillo, 2013; Shapiro, 2016; Knottnerus, 2017; Zanetti, 2019). In addition, one functional study showed that this mutation results in a drastically reduced level of functional protein as well as lowered specific activity (Perkins, 1999). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for the p.S66W alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000255782	SCV004042018	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	SGSH: PM3:Very Strong, PM2, PP3, PP4, PS3:Supporting
Baylor Genetics	RCV000005418	SCV004201070	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-03-29	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000005418	SCV004244436	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-02-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003934800	SCV004756366	pathogenic	SGSH-related disorder	2023-12-12	criteria provided, single submitter	clinical testing	The SGSH c.197C>G variant is predicted to result in the amino acid substitution p.Ser66Trp. This variant was reported in multiple individuals mucopolysaccharidosis type IIIA (Sanfilippo A) (Blanch. 1997. PubMed ID: 9158154; Knottnerus. 2017. PubMed ID: 29023963; Barone. 2021. PubMed ID: 34349725; Table S4, Barbosa-Gouveia. 2021. PubMed ID: 34440436). Functional in vitro studies found this variant has reduced expression and residual activity (Perkins. 1999. PubMed ID: 10601282). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
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	not provided	Mucopolysaccharidosis		no assertion provided	literature only
Natera, Inc.	RCV000005418	SCV001453825	pathogenic	Mucopolysaccharidosis, MPS-III-A	2020-09-16	no assertion criteria provided	clinical testing