Submissions for variant NM_000199.5(SGSH):c.1298G>A (p.Arg433Gln)

gnomAD frequency: 0.00001  dbSNP: rs104894641

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790770	SCV000232481	pathogenic	not provided	2013-12-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000005416	SCV000789552	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2017-02-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000005416	SCV000918204	pathogenic	Mucopolysaccharidosis, MPS-III-A	2017-09-11	criteria provided, single submitter	clinical testing	Variant summary: The SGSH c.1298G>A (p.Arg433Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/120022 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic SGSH variant (0.0032275). The variant has been reported in numerous affected individuals in the literature in both homozygous and compound heterozygous states. Patient fibroblasts as well as transfected cells showed low to non-detectable enzyme activity (Montfort_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV000005416	SCV001394068	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-08-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 433 of the SGSH protein (p.Arg433Gln). This variant is present in population databases (rs104894641, gnomAD 0.004%). This missense change has been observed in individual(s) with Sanfilippo syndrome A (PMID: 11343308, 12702166, 30593151). 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: 5109). 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: 15542396). This variant disrupts the p.Arg433 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11182930, 15542396, 29023963). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000005416	SCV002045482	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512806	SCV003613371	pathogenic	Inborn genetic diseases	2022-03-28	criteria provided, single submitter	clinical testing	The c.1298G>A (p.R433Q) alteration is located in exon 8 (coding exon 8) of the SGSH gene. This alteration results from a G to A substitution at nucleotide position 1298, causing the arginine (R) at amino acid position 433 to be replaced by a glutamine (Q). This alteration has been reported in the homozygous and compound heterozygous states in individuals with phenotypes consistent with mucopolysaccharidosis type IIIA (Chabás, 2001; Di Natale, 2003; Héron, 2011; Shapiro, 2016; Valstar, 2010). Functional studies showed that the p.R433Q alteration demonstrated a lack of enzyme activity (Montfort, 2004). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000005416	SCV003936072	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-06-26	criteria provided, single submitter	clinical testing	A homozygous variation in exon 8 of the SGSH gene that results in the amino acid substitution of Glutamine for Arginine at codon 433 was detected. This variant has not been reported in 1000 genomes and has a MAF of 0.0012% in the gnomAD database. The in-silico prediction is disease causing by MutationTaster, DANN, PolyPhen-2 and SIFT. In summary, the variant meets our criteria to be classified as pathogenic
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000005416	SCV004046399	pathogenic	Mucopolysaccharidosis, MPS-III-A		criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous and a homozygous change in patients with Mucopolysaccharidosis type IIIA (PMID: 11343308, 12702166, 15542396, 30593151, 31236806). Functional studies using patient fibroblasts demonstrated that this variant dramatically reduces the enzymatic activity of sulfamidase. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/250380) and thus is presumed to be rare. The c.1298G>A (p.Arg433Gln) 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.1298G>A (p.Arg433Gln) variant is classified as Pathogenic.
Baylor Genetics	RCV000005416	SCV004201125	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-03-20	criteria provided, single submitter	clinical testing
OMIM	RCV000005416	SCV000025598	pathogenic	Mucopolysaccharidosis, MPS-III-A	2003-04-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000005416	SCV002095112	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-01-27	no assertion criteria provided	clinical testing