ClinVar Miner

Submissions for variant NM_000202.8(IDS):c.263G>A (p.Arg88His)

dbSNP: rs2089497431
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001222779 SCV001394895 pathogenic Mucopolysaccharidosis, MPS-II 2022-03-03 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg88 amino acid residue in IDS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7814022, 8940265, 9950361, 15614569, 17063374, 22990955, 24125893, 26762690). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects IDS function (PMID: 10838181). 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 IDS protein function. ClinVar contains an entry for this variant (Variation ID: 950955). This missense change has been observed in individuals with mucopolysaccharidosis II (PMID: 8940265, 10215411, 24125893, 24515576, 27146977). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 88 of the IDS protein (p.Arg88His).
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences RCV001222779 SCV001479336 pathogenic Mucopolysaccharidosis, MPS-II criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001222779 SCV002014481 pathogenic Mucopolysaccharidosis, MPS-II 2021-09-05 criteria provided, single submitter clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India RCV001222779 SCV002053726 likely pathogenic Mucopolysaccharidosis, MPS-II criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001222779 SCV002572286 pathogenic Mucopolysaccharidosis, MPS-II 2022-08-24 criteria provided, single submitter clinical testing Variant summary: IDS c.263G>A (p.Arg88His) 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 114316 control chromosomes (gnomAD). c.263G>A has been reported in the literature in multiple hemizygous individuals affected with Mucopolysaccharidosis Type II (Hunter Syndrome, e.g. Agrawal_2022, Lampe_2014, Rathmann_1996). These data indicate that the variant is very likely to be associated with disease. In vitro assays using transiently transfected COS7 cells showed that cells transfected with the variant had 13.7% residual enzyme activity compared to cells transfected with wildtype (Villani_2000). Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV001222779 SCV002583235 pathogenic Mucopolysaccharidosis, MPS-II 2022-08-13 criteria provided, single submitter clinical testing A Hemizygous missense variation in exon 3 of the IDS gene that results in the aminoacid substitution of Histidine for Arginine at codon 88 was detected.The observed variant c.263G>A (p.Arg88His) has not been reported in the 1000 genomes and gnomAD databases The in silico prediction of the variant are possibly damaging by FATHMM-MKL, DANN, MutPred, LRT and MutationTaster2. The reference codon is conserved across species.In summary, the variant meets our criteria to be classified as pathogenic.In summary, the variant meets our criteria to be classified as a variant of uncertain significance.
Pediatrics, All India Institute of Medical Sciences, New Delhi RCV001222779 SCV001573786 affects Mucopolysaccharidosis, MPS-II 2014-04-06 no assertion criteria provided research The change c.263G>A (p.R88H) was found to be a missense variant, where the basic polar amino acid Arginine at 88 position was substituted by aromatic basic polar amino acid Histidine. It was detected in the hemizygous condition in three families having patients with MPS-II, of which two have attenuated phenotypes from Madhya Pradesh and Uttar Pradesh while one with severe phenotype from Uttrakhand.

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