Total submissions: 11
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Centre de Génétique Humaine, |
RCV001785635 | SCV007346531 | likely benign | Mucopolysaccharidosis, MPS-II | 2025-03-07 | criteria provided, single submitter | clinical testing | The variant affects a moderately conserved nucleotide (phyloP: 7.23 [-19.0, 10.9]) and a highly conserved amino acid that is part of the sulfatase domain. The physicochemical difference between Gly and Ser is small (Grantham dist: 56 [0-215]). There is 12 occurences (including 2 hemizygotes) in gnomAD v4.1.0 (mostly from european origin, prevalence: 0.001%). The in silico tools predict a deleterious effect (CADD: 23.8, REVEL: 0.923, PolyPhen2 probably damaging, SIFT: deleterious, MutationTaster(v2021): deleterious). One patient is reported with the same variant (PMID : 27848944,suppl. table 3) with a severe phenotype (compared with our patient): congenital multiple arthrogryposis, decreased fetal movements, clubfoot, congenital hip dislocation, multiple contractures, short stature, underweight, and inguinal hernia. The variant is reported on ClinVar as "conflicting classifications of pathogenicity" (VCV000424167.12). Two variants affecting the same amino acid have been reported as LP without much metabolic investigation results: 1. c.934G > T p.(Gly312Cys) is reported in 2 patients with very low/absent IDS enzyme activity (PMID: 22976768, suppl. data 5) but no MPS quantification in the urine is available and no phenotypic description is provided. The variant is reported on ClinVar (VCV003255885.2) as LP with no more evidence than the ACMG criteria (i.e. no metabolic investigations). 2. c.935G > A (p.Gly312Asp) is reported in one patient with a moderate/attenuated form of MPS2 (PMID : 27896113). No IDS enzyme activity nor MPS quantification in the urine is reported. The variant is reported on ClinVar (VCV000221213.3) as LP with no more evidence than the ACMG criteria (i.e. no metabolic investigations). Met ACMG criteria: PS3 (caveat: pseudodeficiency exists), PM1, PM5 (can be discussed since the evidences are limited to ACMG criteria for the two other variants affecting the same aa, and (nearly) no functionnal testing has been performed), PP3, BS2 |
| Revvity Omics, |
RCV001785635 | SCV006316188 | uncertain significance | Mucopolysaccharidosis, MPS-II | 2024-04-18 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001785635 | SCV005766777 | uncertain significance | Mucopolysaccharidosis, MPS-II | 2025-09-08 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 312 of the IDS protein (p.Gly312Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Hunter syndrome (PMID: 27848944). ClinVar contains an entry for this variant (Variation ID: 424167). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt IDS protein function with a positive predictive value of 95%. This variant disrupts the p.Gly312 amino acid residue in IDS. Other variant(s) that disrupt this residue have been observed in individuals with IDS-related conditions (PMID: 22976768, 27896113), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Laboratory of Diagnosis and Therapy of Lysosomal Disorders, |
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) |
| Genomic Medicine Center of Excellence, |
RCV001785635 | SCV004805030 | likely benign | Mucopolysaccharidosis, MPS-II | 2024-03-17 | criteria provided, single submitter | research | |
| Institute of Human Genetics, |
RCV001785635 | SCV004032509 | uncertain significance | Mucopolysaccharidosis, MPS-II | 2023-08-02 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV001785635 | SCV002027034 | uncertain significance | Mucopolysaccharidosis, MPS-II | 2021-09-05 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
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. |
| Gene |
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. |
| Dr. |
RCV005899670 | SCV006992321 | not provided | Nonpapillary renal cell carcinoma | no classification provided | in vitro | ||
| Natera, |
RCV001834576 | SCV002084472 | uncertain significance | Mucopolysaccharidosis, MPS-III-A | 2021-02-03 | no assertion criteria provided | clinical testing |