Submissions for variant NM_000203.5(IDUA):c.1163C>A (p.Thr388Lys)

gnomAD frequency: 0.00001  dbSNP: rs794727896

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723454	SCV000700424	likely pathogenic	not provided	2016-12-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000597524	SCV000796074	uncertain significance	Hurler syndrome	2017-12-07	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249042	SCV001422980	likely pathogenic	Mucopolysaccharidosis type 1	2020-01-13	criteria provided, single submitter	curation	The p.Thr388Lys variant in IDUA has been reported in 1 individual with mucopolysaccharidosis (MPS) (PMID: 27520059) and has been identified in 0.009% (1/10974) of East Asian 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: 198686) as a VUS by Counsyl and as likely pathogenic by EGL Genetic Diagnostics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Thr388Arg, has been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 28752568, 21963080, 28728811; Variation ID: 496834). The presence of this variant in 1 affected homozygote with MPS increases the likelihood that the p.Thr388Lys variant is pathogenic (PMID: 27520059). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PP3, PM3_supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001249042	SCV002241296	pathogenic	Mucopolysaccharidosis type 1	2023-07-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 388 of the IDUA protein (p.Thr388Lys). This variant is present in population databases (rs794727896, gnomAD 0.01%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 27520059, 31194252). ClinVar contains an entry for this variant (Variation ID: 198696). 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 determined to be pathogenic (PMID: 14516901, 17606547, 21253827, 21963080, 28752568). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
Revvity Omics, Revvity	RCV000723454	SCV003809926	uncertain significance	not provided	2023-02-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001249042	SCV005185198	pathogenic	Mucopolysaccharidosis type 1	2024-05-21	criteria provided, single submitter	clinical testing	Variant summary: IDUA c.1163C>A (p.Thr388Lys) results in a non-conservative amino acid change located in the glycosyl hydrolases family 39, N-terminal catalytic domain (IPR049166) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-06 in 153708 control chromosomes (gnomAD). c.1163C>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1 (example: Clarke_2019, Kwak_2016). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1163C>G, p.Thr388Arg), supporting the critical relevance of codon 388 to IDUA protein function. The following publications have been ascertained in the context of this evaluation (PMID: 31194252, 27520059). ClinVar contains an entry for this variant (Variation ID: 198696). Based on the evidence outlined above, the variant was classified as pathogenic.