Submissions for variant NM_000199.5(SGSH):c.220C>T (p.Arg74Cys)

gnomAD frequency: 0.00021  dbSNP: rs104894636

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078354	SCV000227052	pathogenic	not provided	2016-09-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000078354	SCV000321945	pathogenic	not provided	2022-03-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate very low sulfamidase production compared to wild-type (Perkins et al., 1999).; 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: 18407553, 24816101, 11668611, 21061399, 31236806, 28963436, 30809705, 30548430, 10601282, 18392742, 15146460, 11793481, 22976768, 26787381, 21671382, 29023963, 28844463, 9285796, 31718697, 31980526, 32036093, 34349725, 34426522, 31589614, 33726816)
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000005415	SCV000590925	pathogenic	Mucopolysaccharidosis, MPS-III-A	2017-06-07	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000005415	SCV000745252	pathogenic	Mucopolysaccharidosis, MPS-III-A	2015-09-21	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626628	SCV000747329	likely pathogenic	Abnormal circulating carbohydrate concentration	2017-01-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000005415	SCV000782576	pathogenic	Mucopolysaccharidosis, MPS-III-A	2017-01-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000005415	SCV000820679	pathogenic	Mucopolysaccharidosis, MPS-III-A	2025-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 74 of the SGSH protein (p.Arg74Cys). This variant is present in population databases (rs104894636, gnomAD 0.04%). This missense change has been observed in individuals with MPS type IIIA (PMID: 9285796, 9401012, 22976768, 28844463). ClinVar contains an entry for this variant (Variation ID: 5108). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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, 15146460). This variant disrupts the p.Arg74 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been observed in individuals with SGSH-related conditions (PMID: 9401012, 15542396), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000005415	SCV000929892	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2019-01-01	criteria provided, single submitter	literature only	PS3: Low/absent in vivo enzymatic activity in homozygote. PS3: Low in vitro enzymatic activity. PM2: Very low frequency in GnomAD
Myriad Genetics, Inc.	RCV000005415	SCV001194099	pathogenic	Mucopolysaccharidosis, MPS-III-A	2019-12-26	criteria provided, single submitter	clinical testing	NM_000199.3(SGSH):c.220C>T(R74C) is classified as pathogenic in the context of mucopolysaccharidosis type IIIA. Sources cited for classification include the following: PMID 9401012, 15146460, 11182930, 18407553, 24314109, 21061399 and 11182930. Classification of NM_000199.3(SGSH):c.220C>T(R74C) 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	RCV000078354	SCV001247663	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	SGSH: PM3:Very Strong, PM2, PM5, PP3, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000005415	SCV001366179	pathogenic	Mucopolysaccharidosis, MPS-III-A	2018-09-25	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3,PP4.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000005415	SCV001548177	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-03-25	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000005415	SCV002021245	pathogenic	Mucopolysaccharidosis, MPS-III-A	2019-10-09	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000005415	SCV002045508	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000005415	SCV002813133	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-05-25	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000005415	SCV003843893	pathogenic	Mucopolysaccharidosis, MPS-III-A	2011-06-16	criteria provided, single submitter	clinical testing	A Heterozygous missense variation in exon 2 of the SGSH gene that results in the amino acid substitution of Cystine for Arginine at codon 74 was detected. The observed variant c.220C>T (p.Arg74Cys) has not been reported in the 1000 genomes and has a MAF of 0.02% in gnomAD databases. The in silico prediction of the variant are possibly damaging by LRT, SIFT and MutationTaster. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
Baylor Genetics	RCV000005415	SCV004201087	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-03-28	criteria provided, single submitter	clinical testing
OMIM	RCV000005415	SCV000025597	pathogenic	Mucopolysaccharidosis, MPS-III-A	1997-01-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000005415	SCV000733744	pathogenic	Mucopolysaccharidosis, MPS-III-A		no assertion criteria provided	clinical testing
GeneReviews	RCV001030813	SCV001194302	not provided	Mucopolysaccharidosis		no assertion provided	literature only
Natera, Inc.	RCV000005415	SCV001453824	pathogenic	Mucopolysaccharidosis, MPS-III-A	2020-09-16	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000005415	SCV001760415	pathogenic	Mucopolysaccharidosis, MPS-III-A		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078354	SCV002037524	pathogenic	not provided		no assertion criteria provided	clinical testing