Submissions for variant NM_000199.5(SGSH):c.544C>T (p.Arg182Cys)

gnomAD frequency: 0.00001  dbSNP: rs529855742

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000626217	SCV000746862	pathogenic	Mucopolysaccharidosis, MPS-III-A	2017-12-18	criteria provided, single submitter	clinical testing
Center for Medical Genetics, GenVams Trust	RCV000626217	SCV000897637	pathogenic	Mucopolysaccharidosis, MPS-III-A		criteria provided, single submitter	clinical testing	The Arg182Cys variant in SGSH has been reported in a hetoroallelic Italian patient. In the patient, the variant caused absence of restriction site of MspA11 enzyme. This cleaved the 296 bp segment to 200 and 96 bp segments. This study also noted the phenotype to be intermediate in terms of severity (di Natale et al, 1998). However, our patient, being homozygous for the Arg182Cs variant, showed intermediate-severe phenotype. The Arg182Cys variant has not been reported in the testing organization's (secondary organization here) internal database and has a minor allele frequency of 0.02% and 0.0008% in the 1000 genomes and ExAC databases respectively. The in silico prediction of the variant is probably damaging by PolyPhen-2 (HumDiv) and damaging by LRT, SIFT and MutationTaster2.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000626217	SCV000929897	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2019-01-01	criteria provided, single submitter	literature only	PS3: Low in vitro enzymatic activity. PM2: Very low frequency in ExAc
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000626217	SCV002015190	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-10-06	criteria provided, single submitter	clinical testing	Variant summary: SGSH c.544C>T (p.Arg182Cys) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 244306 control chromosomes. c.544C>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (example, Di Natale_1998, Valstar_2010, Heron_2011, Zanetti_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal Sulfamidase enzyme activity in a homozygous patient (example, Zanetti_2019). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000626217	SCV002045502	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV002285381	SCV002575808	likely pathogenic	not provided	2022-03-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 21061399, 25807448, 9554748, 24816101)
Fulgent Genetics, Fulgent Genetics	RCV000626217	SCV002811673	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-03-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000626217	SCV003442422	pathogenic	Mucopolysaccharidosis, MPS-III-A	2022-09-27	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 182 of the SGSH protein (p.Arg182Cys). This variant is present in population databases (rs529855742, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis IIIA (PMID: 9554748, 21061399, 30809705). 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: 523015). 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. Experimental studies have shown that this missense change affects SGSH function (PMID: 10727844). For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000626217	SCV004046388	pathogenic	Mucopolysaccharidosis, MPS-III-A		criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous change in a patient with Mucopolysaccharidosis type IIIA (PMID: 21061399). In addition, another missense variant at this position, p.Arg182His, has been reported as a compound heterozygous change in a patient with Mucopolysaccharidosis type IIIA (PMID: 31718697). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/244306) and thus is presumed to be rare. The c.544C>T (p.Arg182Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.544C>T (p.Arg182Cys) variant is classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000626217	SCV004171124	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-11-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000626217	SCV004201082	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-11-11	criteria provided, single submitter	clinical testing