ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.1898C>T (p.Ser633Leu)

gnomAD frequency: 0.00001  dbSNP: rs886043347
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672407 SCV000797508 pathogenic Hurler syndrome 2018-01-30 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001380047 SCV001577977 pathogenic Mucopolysaccharidosis type 1 2023-11-29 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 633 of the IDUA protein (p.Ser633Leu). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis (PMID: 11735025, 16438163, 21480867, 26825088, 27146977). ClinVar contains an entry for this variant (Variation ID: 556406). 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. Experimental studies have shown that this missense change affects IDUA function (PMID: 11735025). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002499181 SCV002810317 pathogenic Mucopolysaccharidosis, MPS-I-S; Hurler syndrome; Mucopolysaccharidosis, MPS-I-H/S 2022-03-09 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV004817901 SCV005439044 pathogenic Mucopolysaccharidosis, MPS-I-H/S 2023-06-22 criteria provided, single submitter clinical testing The observed missense c.1898C>Tp.Ser633Leu variant in IDUA gene has been reported previously in multiple individuals affected with mucopolysaccharidosis Uttarilli A, et al., 2016; Kunin-Batson AS, et al., 2016; Wang X, et al., 2012; Beesley CE, et al., 2001. Experimental studies have shown that this missense change affects IDUA function Beesley CE, et al., 2001. The p.Ser633Leu variant has been reported with allele frequency of 0.001% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic multiple submissions. Multiple lines of computational evidences Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid change at this position on IDUA gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 633 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as pathogenic. In absence of another reportable variant in IDUA gene, the molecular diagnosis is not confirmed.
Natera, Inc. RCV001380047 SCV002075394 pathogenic Mucopolysaccharidosis type 1 2020-04-09 no assertion criteria provided clinical testing

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