Submissions for variant NM_000203.5(IDUA):c.1163C>G (p.Thr388Arg)

gnomAD frequency: 0.00001  dbSNP: rs794727896

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723433	SCV000700359	likely pathogenic	not provided	2017-01-13	criteria provided, single submitter	clinical testing
Counsyl	RCV000592196	SCV000789402	likely pathogenic	Hurler syndrome	2017-02-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001215791	SCV001387553	pathogenic	Mucopolysaccharidosis type 1	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 388 of the IDUA protein (p.Thr388Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis Type I (PMID: 14516901, 17606547, 21253827, 21963080, 28752568). ClinVar contains an entry for this variant (Variation ID: 496834). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDUA protein function. This variant disrupts the p.Thr388 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been observed in individuals with IDUA-related conditions (PMID: 27520059), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001215791	SCV001422981	pathogenic	Mucopolysaccharidosis type 1	2020-01-14	criteria provided, single submitter	curation	The p.Thr388Arg variant in IDUA has been reported in at least 9 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 21963080, 28728811, 21253827) and has been identified in 0.001% (1/74540) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs794727896). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 496834) as likely pathogenic by EGL Genetic Diagnostics and Counsyl. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with reported pathogenic variants in at least 7 individuals with MPS increases the likelihood that the p.Thr388Arg variant is pathogenic (VariationID: 11908, 11910, 550799, 11917; PMID: 28752568, 21963080, 28728811, 21253827). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the presence of the variant in combination with other pathogenic variants in individuals with MPS, its low frequency in the general population, and computational evidence. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP3 (Richards 2015).
Revvity Omics, Revvity	RCV000723433	SCV002016681	likely pathogenic	not provided	2023-08-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001215791	SCV002600295	pathogenic	Mucopolysaccharidosis type 1	2022-10-05	criteria provided, single submitter	clinical testing	Variant summary: IDUA c.1163C>G (p.Thr388Arg) results in a non-conservative amino acid change in 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 153708 control chromosomes. c.1163C>G has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 (e.g. Wang_2011, Ghosh_2017). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV001215791	SCV002075339	pathogenic	Mucopolysaccharidosis type 1	2020-01-18	no assertion criteria provided	clinical testing