Submissions for variant NM_000202.8(IDS):c.890G>A (p.Arg297His)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470647	SCV002768902	uncertain significance	Mucopolysaccharidosis, MPS-II	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mucopolysaccharidosis II (MPS II) (MIM#309900). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (0 heterozygotes, 0 homozygotes, 1 hemizygotes). (SP) 0309 - An alternative amino acid change, p.(Arg297Cys) at the same position has been observed in gnomAD (v2) (5 heterozygotes, 0 homozygotes, 4 hemizygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated sulfatase domain (Pfam). (I) 0701 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. Thep.(Arg297Gly) has previously been reported with unknown significance in one hemizygous male with normal glycosaminoglyacan levels (PMID:33124617). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It is commonly reported as a pseudodeficiency variant (PMIDs: 30409495; 31877959; 3311790; 33124617). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is inconclusive. Lin et al suggest that this variant may contribute to an attenuated form of MPS II or no phenotype at all (PMIDs: 31877959; 33096603). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV002470647	SCV003450992	uncertain significance	Mucopolysaccharidosis, MPS-II	2022-09-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 297 of the IDS protein (p.Arg297His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with mucopolysaccharidosis type II (PMID: 29801497). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV002470647	SCV003817551	uncertain significance	Mucopolysaccharidosis, MPS-II	2023-08-03	criteria provided, single submitter	clinical testing