Submissions for variant NM_000202.8(IDS):c.934G>A (p.Gly312Ser)

dbSNP: rs903259179

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481557	SCV000573952	uncertain significance	not provided	2018-03-08	criteria provided, single submitter	clinical testing	The G312S variant in the IDS gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G312S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G312S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (G312C, G312D) have been reported previously, in individuals with mucopolysaccharidosis II (Pollard et al., 2013; Amartino et al., 2014). Additionally, missense variants in nearby residues (D308Y, D308N, D308E, T309A, R313C, L314P, L314H) have also been reported in the Human Gene Mutation Database in association with a mucopolysaccharidosis II (Stenson et al., 2014). These variants support the functional importance of this region of the protein. We interpret G312S as a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293485	SCV001482065	uncertain significance	not specified	2023-10-10	criteria provided, single submitter	clinical testing	Variant summary: IDS c.934G>A (p.Gly312Ser) 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 was absent in 183438 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.934G>A has been reported in the literature in a sample suspected of Mucopolysaccharidosis Type II from clinical exome sequencing cases (Truijillano_2017). This report however, does not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type II (Hunter Syndrome). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 27848944). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV001785635	SCV002027034	uncertain significance	Mucopolysaccharidosis, MPS-II	2021-09-05	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV001785635	SCV004032509	uncertain significance	Mucopolysaccharidosis, MPS-II	2023-08-02	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001785635	SCV004805030	likely benign	Mucopolysaccharidosis, MPS-II	2024-03-17	criteria provided, single submitter	research
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001785635	SCV005089316	likely pathogenic	Mucopolysaccharidosis, MPS-II	2024-06-07	criteria provided, single submitter	literature only	Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Supporting), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Missense variant in a gene with a low rate of benign missense variation (PP2_Supporting), Multiple lines of computational evidence support a deleterious effect (PP3_Supporting), Patient’s phenotype or family history highly specific for the disease (PP4_Strong)
Natera, Inc.	RCV001834576	SCV002084472	uncertain significance	Mucopolysaccharidosis, MPS-III-A	2021-02-03	no assertion criteria provided	clinical testing