Submissions for variant NM_000202.8(IDS):c.328A>G (p.Arg110Gly)

dbSNP: rs2124063287

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378371	SCV001575923	likely pathogenic	Mucopolysaccharidosis, MPS-II	2021-09-24	criteria provided, single submitter	clinical testing	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 sequence change replaces arginine with glycine at codon 110 of the IDS protein (p.Arg110Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis II (PMID: 30639582; Invitae). 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. Experimental studies have shown that this missense change affects IDS protein function (PMID: 30639582). This variant disrupts the p.Arg110 amino acid residue in IDS. Other variant(s) that disrupt this residue have been observed in individuals with IDS-related conditions (PMID: 27246110), which suggests that this may be a clinically significant amino acid residue.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV001378371	SCV005088992	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), 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_Strong)
GeneDx	RCV004720886	SCV005327600	likely pathogenic	not provided	2023-10-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging significant effect on activity and expression in vitro (Zhang et al., 2019); Previously reported in an individual with mucopolysaccharidosis type II, with neurologic involvement, in the published literature (Zhang et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27246110, 30639582)