Submissions for variant NM_000199.5(SGSH):c.734G>A (p.Arg245His)

gnomAD frequency: 0.00039  dbSNP: rs104894635

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078356	SCV000231496	pathogenic	not provided	2015-10-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000078356	SCV000321946	pathogenic	not provided	2021-12-29	criteria provided, single submitter	clinical testing	Published functional studies found R245H is associated with significantly reduced sulfamidase activity (Perkins et al., 1999); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18407553, 11182930, 25807448, 19383612, 21671382, 21061399, 10601282, 26331342, 9285796, 9158154, 24816101, 26787381, 27590925, 21228398, 31718697, 31980526, 32036093, 31589614, 12490062, 31031587, 33726816, 29023963)
Illumina Laboratory Services, Illumina	RCV000005414	SCV000407358	pathogenic	Mucopolysaccharidosis, MPS-III-A	2017-04-27	criteria provided, single submitter	clinical testing	The SGSH c.734G>A (p.Arg245His) variant is one of the most commonly detected variants in individuals with mucopolysaccharidosis type III, accounting for up to 58% of disease alleles in some European populations (Fedele et al. 2015). Across a selection of the available literature, the p.Arg245His variant has been identified in a homozygous state in 37 individuals, in a compound heterozygous state in 75 individuals, and in a heterozygous state in two individuals (Blanch et al. 1997; Weber et al. 1998; Meyer et al. 2008; Valstar et al. 2010; Wilkin et al. 2016). The variant was absent from 20 control alleles but is reported at a frequency of 0.00060 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Arg245 residue is not conserved among human sulphatases. Functional studies showed that the p.Arg245His variant protein is expressed at a lower level than wild type, affects protein stability, and results in 83% of normal activity (Perkins et al. 1999; Sidhu et al. 2014). Based on the collective evidence, the p.Arg245His 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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000078356	SCV000610021	pathogenic	not provided	2017-05-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000348775	SCV000695960	pathogenic	Sanfilippo syndrome	2016-06-26	criteria provided, single submitter	clinical testing	Variant summary: The SGSH c.734G>A (p.Arg245His) variant causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 30/72670 (1/2422), which does not exceed the estimated maximal expected allele frequency for a pathogenic SGSH variant of 1/309. The variant of interest has been reported in multiple affected individuals as homozygotes and compound heterozygotes via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
Ambry Genetics	RCV000623663	SCV000741895	pathogenic	Inborn genetic diseases	2014-09-07	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000005414	SCV000745249	pathogenic	Mucopolysaccharidosis, MPS-III-A	2015-09-21	criteria provided, single submitter	clinical testing
Invitae	RCV000005414	SCV000833727	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 245 of the SGSH protein (p.Arg245His). This variant is present in population databases (rs104894635, gnomAD 0.07%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIA (PMID: 9158154, 9700599, 15146460, 21061399, 22976768, 26331342). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5107). 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). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000005414	SCV000929899	pathogenic	Mucopolysaccharidosis, MPS-III-A	2019-01-01	criteria provided, single submitter	literature only	PS3: Low/absent in vivo enzymatic activity in homozygote; Low in vitro enzymatic activity. PS4: The prevalence of the variant in affected individuals is significantly increase compared with the prevalence in controls. PM2: Absent from GnomAD
Baylor Genetics	RCV000005414	SCV001163432	pathogenic	Mucopolysaccharidosis, MPS-III-A		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000005414	SCV001194004	pathogenic	Mucopolysaccharidosis, MPS-III-A	2019-12-20	criteria provided, single submitter	clinical testing	NM_000199.3(SGSH):c.734G>A(R245H) is classified as pathogenic in the context of mucopolysaccharidosis type IIIA. Sources cited for classification include the following: PMID 22976788, 21061399, 26787381 and 10601282. Classification of NM_000199.3(SGSH):c.734G>A(R245H) 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.
CeGaT Center for Human Genetics Tuebingen	RCV000078356	SCV001247662	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	SGSH: PM3:Very Strong, PM2, PM5
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000005414	SCV001548176	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-03-25	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000005414	SCV002021244	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-05-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000005414	SCV002045495	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000005414	SCV002095589	pathogenic	Mucopolysaccharidosis, MPS-III-A	2022-02-11	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000005414	SCV002761682	pathogenic	Mucopolysaccharidosis, MPS-III-A	2019-07-15	criteria provided, single submitter	clinical testing	PS3, PS4, PP3
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000005414	SCV004047988	pathogenic	Mucopolysaccharidosis, MPS-III-A		criteria provided, single submitter	clinical testing	The c.734G>A(p.Arg245His) missense variant in SGSH gene has been reported in individuals affected with mucopolysaccharidosis type IIIA (Wilkin et al., 2016). Experimental studies have shown that this missense change affects SGSH function (Perkins et al., 1999). This variant is reported with the allele frequency (0.03%) in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Arg at position 245 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003415657	SCV004118450	pathogenic	SGSH-related condition	2023-04-19	criteria provided, single submitter	clinical testing	The SGSH c.734G>A variant is predicted to result in the amino acid substitution p.Arg245His. This variant was documented to be pathogenic for Sanfilippo syndrome type A (Blanch et al. 1997. PubMed ID: 9158154; Nijmeijer et al. 2019. PubMed ID: 31718697; Ugrinov et al. 2015. PubMed ID: 25807448). At PreventionGenetics, we have also previously identified this variant in affected patients. This variant is reported in 0.065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-78187614-C-T). This variant is interpreted as pathogenic.
OMIM	RCV000005414	SCV000025596	pathogenic	Mucopolysaccharidosis, MPS-III-A	1998-06-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000005414	SCV000733741	pathogenic	Mucopolysaccharidosis, MPS-III-A		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000078356	SCV000801902	pathogenic	not provided	2017-04-19	no assertion criteria provided	clinical testing
GeneReviews	RCV001030817	SCV001194306	not provided	Mucopolysaccharidosis		no assertion provided	literature only
Natera, Inc.	RCV000005414	SCV001463880	pathogenic	Mucopolysaccharidosis, MPS-III-A	2020-09-16	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000005414	SCV001760413	likely pathogenic	Mucopolysaccharidosis, MPS-III-A		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078356	SCV001959607	pathogenic	not provided		no assertion criteria provided	clinical testing
Institute of Human Genetics, University of Wuerzburg	RCV001837434	SCV002098144	pathogenic	Neurodegeneration		no assertion criteria provided	clinical testing