Submissions for variant NM_000202.8(IDS):c.670G>A (p.Gly224Arg)

dbSNP: rs2089450754

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193752	SCV001362834	uncertain significance	not specified	2019-09-02	criteria provided, single submitter	clinical testing	Variant summary: IDS c.670G>A (p.Gly224Arg) results in a non-conservative amino acid change located in the Sulfatase, N-terminal 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 183383 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.670G>A in individuals affected with Mucopolysaccharidosis Type II (Hunter Syndrome) have been reported. However, a different nucleotide change resulting in the same amino acid change has been reported in an MPS II patient (Kosuga_2016). To our knowledge no experimental evidence demonstrating the variants impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001376882	SCV001574068	likely pathogenic	Mucopolysaccharidosis, MPS-II	2020-07-02	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Gly224 amino acid residue in IDS. Other variant(s) that disrupt this residue have been observed in individuals with IDS-related conditions (PMID: 9921913, 22990955), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This missense change has been observed in individual(s) with mucopolysaccharidosis II (PMID: 27246110, Invitae). This sequence change replaces glycine with arginine at codon 224 of the IDS protein (p.Gly224Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency).
Genome-Nilou Lab	RCV001376882	SCV002014456	likely pathogenic	Mucopolysaccharidosis, MPS-II	2021-09-05	criteria provided, single submitter	clinical testing