Submissions for variant NM_000199.5(SGSH):c.221G>A (p.Arg74His)

dbSNP: rs778336949

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665263	SCV000789354	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2017-01-30	criteria provided, single submitter	clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000665263	SCV000929893	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2019-01-01	criteria provided, single submitter	literature only	PS3: Low in vitro enzymatic activity. PM2: Absent from GnomAD
Labcorp Genetics (formerly Invitae), Labcorp	RCV000665263	SCV000936017	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-05-07	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 74 of the SGSH protein (p.Arg74His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with MPS IIIA (PMID: 9401012, 11343308; Invitae). 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: 550504). 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%. This variant disrupts the p.Arg74 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9285796, 9401012, 11343308, 22976768, 28844463). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000665263	SCV001774435	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-08-03	criteria provided, single submitter	clinical testing	Variant summary: SGSH c.221G>A (p.Arg74His) 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 4.7e-06 in 211504 control chromosomes (gnomAD and publication data). c.221G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A), including at least two homozygotes (Bunge_1997, Chabas_2001, Montfort_2004). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant results in reducing sulfamidase activity compared to WT activity (Montfort_2004). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000665263	SCV002045507	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000665263	SCV004201068	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-12-17	criteria provided, single submitter	clinical testing
GeneDx	RCV004719928	SCV005324843	pathogenic	not provided	2023-08-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the variant results in significantly decreased enzyme activity (PMID: 15542396); 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: 24816101, 16174644, 9401012, 15542396)
Neuberg Centre For Genomic Medicine, NCGM	RCV000665263	SCV005438839	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-07-22	criteria provided, single submitter	clinical testing	The observed missense c.221G>Ap.Arg74His variant in SGSH gene has been reported previously in homozygous or compound heterozygous state in individuals affected with Mucopolysaccharidoses MPS Zanetti et al., 2019. This variant is reported with the allele frequency of 0.0004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic / Likely Pathogenic multiple submissions. The amino acid Arg at position 74 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg74His in SGSH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence Polyphen - Damaging, SIFT - Damaging, and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. For these reasons, this variant has been classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004756002	SCV005367288	pathogenic	SGSH-related disorder	2024-07-17	no assertion criteria provided	clinical testing	The SGSH c.221G>A variant is predicted to result in the amino acid substitution p.Arg74His. This variant, also referred to as R74H, has been reported in the homozygous state in several individuals with a diagnosis or clinical features suggestive of mucopolysaccharidosis type IIIA (MPS IIIA), also known as Sanfilippo syndrome A (Bunge et al. 1997. PubMed ID: 9401012; Chabás et al. 2001. PubMed ID: 11343308; Gul et al. 2023. PubMed ID: 37772257). It was also reported along with a second pathogenic SGSH variant in a patient with MPS IIIA (Chabás et al. 2001. PubMed ID: 11343308). A different missense change impacting the same amino acid (c.220C>T; p.Arg74Cys) has been reported in individuals with MPS IIIA (Weber et al. 1997. PubMed ID: 9285796; Yassaee et al. 2017. PubMed ID: 28844463). This amino acid residue is highly conserved and is a critical component to the protein's active site; changes to this amino acid result in decreased enzyme stability and disruption of ion binding (Sidhu et al. 2014. PubMed ID: 24816101). This variant is reported in 0.0037% of alleles in individuals of South Asian descent in gnomAD; however, the quality of this data is questionable and should be treated with caution. This variant is interpreted as pathogenic.