Submissions for variant NM_000199.5(SGSH):c.268G>A (p.Gly90Arg)

gnomAD frequency: 0.00001  dbSNP: rs774010006

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665315	SCV000789415	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2017-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000665315	SCV001362833	pathogenic	Mucopolysaccharidosis, MPS-III-A	2019-11-15	criteria provided, single submitter	clinical testing	Variant summary: SGSH c.268G>A (p.Gly90Arg) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain 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 8e-06 in 248612 control chromosomes (gnomAD). c.268G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A)(Bunge_1997, Sun_2011, Heron_2011, Chistiakov_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000665315	SCV001372574	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-09-08	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with clinical features of SGSH-related conditions (PMID: 21204211, 21455105, 24875751). This variant is present in population databases (rs774010006, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 90 of the SGSH protein (p.Gly90Arg). ClinVar contains an entry for this variant (Variation ID: 550542). For these reasons, this variant has been classified as Pathogenic. 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.
Genome-Nilou Lab	RCV000665315	SCV002045506	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000665315	SCV004201097	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-01-15	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000665315	SCV005438840	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-07-22	criteria provided, single submitter	clinical testing	The observed missense c.268G>Ap.Gly90Arg variant in SGSH gene has been reported previously in homozygous or compound heterozygous state in individuals affected with Mucopolysaccharidosis type IIIA Ugrinov et al., 2015. This variant is reported with the allele frequency of 0.0008% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic. The amino acid Gly at position 90 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly90Arg 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.