Submissions for variant NM_000202.8(IDS):c.1122C>T (p.Gly374=)

dbSNP: rs113993948

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
IIFP, CONICET-UNLP	RCV000011237	SCV000262535	pathogenic	Mucopolysaccharidosis, MPS-II	2007-11-13	criteria provided, single submitter	research
Invitae	RCV000011237	SCV000628120	pathogenic	Mucopolysaccharidosis, MPS-II	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change affects codon 374 of the IDS mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the IDS protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 20 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in the activation of a cryptic splice site in exon 8 (PMID: 8940265, 26407519, 26693516). ClinVar contains an entry for this variant (Variation ID: 10491). This variant is also known as c.1246C>T. This variant has been observed in individuals with mucopolysaccharidosis type II (PMID: 8940265, 16133661, 17063374, 21829674, 22976768, 27146977). This variant is not present in population databases (gnomAD no frequency).
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	RCV000011237	SCV001480480	likely pathogenic	Mucopolysaccharidosis, MPS-II		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000011237	SCV002014472	pathogenic	Mucopolysaccharidosis, MPS-II	2021-09-05	criteria provided, single submitter	clinical testing
GeneDx	RCV002284352	SCV002574624	pathogenic	not provided	2022-09-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that this variant creates a new splice donor site resulting in skipping of the last 60 nucleotides of exon 8 (Matos et al. 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 8940265, 8281149, 21829674, 16133661, 26407519, 1639384, 17063374, 9921913, 16495038, 30639582, 21291454, 27146977, 11462244, 33676511, 35144014, 34006472, 31877959, 26693516)
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000011237	SCV004040634	likely pathogenic	Mucopolysaccharidosis, MPS-II	2023-09-23	criteria provided, single submitter	clinical testing	A hemizygous variant in exon 8 of the IDS gene that results in the amino acid substitution of Glycine for Glycine at codon 374 was detected. The observed variant c.1122C>T has not been reported in the 1000 genomes and gnomAD databases. The in-silico prediction of the variant is damaging by Splice AI tool. In summary, the variant meets our criteria to be classified as likely pathogenic.
Illumina Laboratory Services, Illumina	RCV000011237	SCV004101336	pathogenic	Mucopolysaccharidosis, MPS-II	2023-09-07	criteria provided, single submitter	clinical testing	The IDS c.1122C>T p.(Gly374=) synonymous variant is one of the most commonly reported disease-causing variants in IDS. This variant has been identified in individuals with mucopolysaccharidosis type II (MPSII) and was reported in a de novo state in at least one of these individuals (PMID: 8940265; 20301451; 27146977; 30639582; 31877959; 33676511; 34006472). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies show that the c.1122C>T variant results in activation of a cryptic splice site within exon 8 of the IDS gene leading to a deletion of 20 amino acids (PMID: 8940265; 26407519; 26693516). Based on the available evidence, the c.1122C>T p.(Gly374=) variant is classified as pathogenic for mucopolysaccharidosis type II.
OMIM	RCV000011237	SCV000031464	pathogenic	Mucopolysaccharidosis, MPS-II	1992-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000011237	SCV000999929	not provided	Mucopolysaccharidosis, MPS-II		no assertion provided	literature only
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	RCV000011237	SCV001482353	pathogenic	Mucopolysaccharidosis, MPS-II	2019-05-31	no assertion criteria provided	research
Pediatrics, All India Institute of Medical Sciences, New Delhi	RCV000011237	SCV001573802	affects	Mucopolysaccharidosis, MPS-II	2014-04-13	no assertion criteria provided	research	The change c.1122C>T is a known cryptic splice generator variant. This mutation is due to the substitution of C to T at nucleotide position c.11122 in the exon 8 of IDS gene. In the present study, it was detected in a hemizygous state in one of the patient with severe phenotype from Delhi, India. Uttarilli et al., 2016 described its presence in six MPS II patients of which four with severe phenotype and two with an attenuated phenotype.