Total submissions: 12
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000180473 | SCV005725853 | pathogenic | Mucopolysaccharidosis, MPS-II | 2024-11-25 | criteria provided, single submitter | clinical testing | Variant summary: IDS c.1403G>A (p.Arg468Gln) results in a conservative amino acid change located in the iduronate-2-sulfatase domain (IPR035874) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183290 control chromosomes. c.1403G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type II (Hunter Syndrome) (example, Muenzer_2024, Sukegawa_1997). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1402C>T, p.Arg468Trp), supporting the critical relevance of codon 468 to IDS protein function. At least one publication reports experimental evidence evaluating an impact on protein function ( Sukegawa_1997). The most pronounced variant effect results in diminished IDS activity in patients' cells. The following publications have been ascertained in the context of this evaluation (PMID: 39303318, 9375851). ClinVar contains an entry for this variant (Variation ID: 10498). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Gene |
RCV000790797 | SCV005421302 | pathogenic | not provided | 2024-06-03 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10838181, 34813777, 35144014, 22990955, 15614569, 17091340, 8364592, 26762690, 28077157, 27187040, 27695081, 30639582, 31877959, 33676511) |
| Labcorp Genetics |
RCV000180473 | SCV004299009 | pathogenic | Mucopolysaccharidosis, MPS-II | 2023-07-25 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg468 amino acid residue in IDS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1284597, 15614569, 28077157, 30639582). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects IDS function (PMID: 18500569). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDS protein function. ClinVar contains an entry for this variant (Variation ID: 10498). This missense change has been observed in individuals with mucopolysaccharidosis II (PMID: 7581397, 9266380, 9875019). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 468 of the IDS protein (p.Arg468Gln). |
| Foundation for Research in Genetics and Endocrinology, |
RCV000180473 | SCV003915848 | pathogenic | Mucopolysaccharidosis, MPS-II | 2023-03-22 | criteria provided, single submitter | clinical testing | A hemizygous variation in exon 9 of the IDS gene detected. The observed variant c.1403G>A has not been reported in the 1000 genomes databases. The in silico prediction is damaging by SIFT, PROVEAN, Polyphen2 and MutationTaster. In summary, the variant meets our criteria to be classified as pathogenic. |
| Revvity Omics, |
RCV000180473 | SCV003825334 | pathogenic | Mucopolysaccharidosis, MPS-II | 2022-10-13 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV000180473 | SCV002014467 | pathogenic | Mucopolysaccharidosis, MPS-II | 2021-09-05 | criteria provided, single submitter | clinical testing | |
| Department of Medical Genetics, |
RCV000180473 | SCV001480198 | pathogenic | Mucopolysaccharidosis, MPS-II | criteria provided, single submitter | clinical testing | ||
| Laboratory of Diagnosis and Therapy of Lysosomal Disorders, |
RCV000180473 | SCV000929887 | pathogenic | Mucopolysaccharidosis, MPS-II | 2024-06-07 | criteria provided, single submitter | literature only | In vitro or in vivo functional studies supportive of a damaging effect (PS3_Moderate), Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Strong), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Cosegregation with disease in multiple affected family members (PP1_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_Moderate) |
| IIFP, |
RCV000180473 | SCV000262515 | pathogenic | Mucopolysaccharidosis, MPS-II | 2007-08-02 | criteria provided, single submitter | research | |
| Eurofins Ntd Llc |
RCV000790797 | SCV000232923 | pathogenic | not provided | 2013-09-25 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000180473 | SCV000999927 | not provided | Mucopolysaccharidosis, MPS-II | no assertion provided | literature only | ||
| OMIM | RCV000011244 | SCV000031471 | pathogenic | Mucopolysaccharidosis type 2, severe form | 1997-01-01 | no assertion criteria provided | literature only |