Submissions for variant NM_000202.8(IDS):c.262C>T (p.Arg88Cys)

dbSNP: rs398123249

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790676	SCV000228818	pathogenic	not provided	2013-01-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000177014	SCV000628121	pathogenic	Mucopolysaccharidosis, MPS-II	2017-07-26	criteria provided, single submitter	clinical testing	A different missense substitution at this codon (p.Arg88His) has been determined to be pathogenic (PMID: 9921913, 9660053, 10215411, 10838181, 24515576). This suggests that the arginine residue is critical for IDS protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects IDS post-translational modification and results in a protein with an almost undetectable enzymatic activity (PMID: 15614569, 22990955). This variant has been reported in several individuals affected with mucopolysaccharidosis type II (PMID: 7814022, 8940265 , 9950361 , 15614569, 17063374, 22990955, 24125893, 26762690). ClinVar contains an entry for this variant (Variation ID: 92618). While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces arginine with cysteine at codon 88 of the IDS protein (p.Arg88Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine.
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	RCV000177014	SCV001480189	pathogenic	Mucopolysaccharidosis, MPS-II		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000177014	SCV002014482	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	RCV000177014	SCV002053817	pathogenic	Mucopolysaccharidosis, MPS-II		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000177014	SCV002103402	pathogenic	Mucopolysaccharidosis, MPS-II	2022-02-23	criteria provided, single submitter	clinical testing	Variant summary: IDS c.262C>T (p.Arg88Cys) 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.262C>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type II (Hunter Syndrome) (e.g. Parkinson_2004, Chang_2005, Froissart_2007, Charoenwattanasatien_2012, Dvorakova_2017). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant confers very little residual IDS activity (Chang_2005, Charoenwattanasatien_2012). Two ClinVar submitters (evaluation after 2014) cite 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	RCV000177014	SCV002583505	pathogenic	Mucopolysaccharidosis, MPS-II	2022-09-01	criteria provided, single submitter	clinical testing	The hemizygous status for variant c.262C>T(p.Arg88Cys) in exon 3 of IDS gene. The variant has not been repoted in the 1000 genome gnomAD databases. The in silico prediction is damaging by DANN, LRT, SIFT and MutationTaster.
Revvity Omics, Revvity	RCV000177014	SCV003825279	pathogenic	Mucopolysaccharidosis, MPS-II	2022-06-30	criteria provided, single submitter	clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000177014	SCV005088943	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_Strong), 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), 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_Strong)
GeneDx	RCV000790676	SCV005201690	pathogenic	not provided	2023-06-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced IDS enzyme activity (Chang et al., 2005; Charoenwattanasatien et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7814022, 22990955, 15614569, 35144014, 32036093, 27695081, 33676511, 30639582, 34813777, 26762690, 31877959)