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

dbSNP: rs2089497431

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001222779	SCV001394895	pathogenic	Mucopolysaccharidosis, MPS-II	2022-03-03	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 950955). 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. Experimental studies have shown that this missense change affects IDS function (PMID: 10838181). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This missense change has been observed in individuals with mucopolysaccharidosis II (PMID: 8940265, 10215411, 24125893, 24515576, 27146977). 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). This variant is not present in population databases (gnomAD no frequency). 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.
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.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001222779	SCV005088946	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_Strong), Located in a mutational hot spot and/or critical functional domain (PM1_Moderate), 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_Moderate)
Division of Medical Genetics, Department of 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.