ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.1577T>C (p.Leu526Pro)

gnomAD frequency: 0.00035  dbSNP: rs781136336
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000687687 SCV000815272 pathogenic Mucopolysaccharidosis type 1 2024-01-21 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 526 of the IDUA protein (p.Leu526Pro). This variant is present in population databases (rs781136336, gnomAD 0.07%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 22976768, 30442156; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 567566). 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. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001566840 SCV001790419 likely pathogenic not provided 2021-07-12 criteria provided, single submitter clinical testing Observed in apparent homozygous state through newborn screening in an infant with >50% enzymatic activity (Donati et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33072983, 32432561, 33147872, 27535533, 30442156, 22976768, 26260077, 30093709)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000687687 SCV002051104 likely pathogenic Mucopolysaccharidosis type 1 2024-08-20 criteria provided, single submitter clinical testing Variant summary: IDUA c.1577T>C (p.Leu526Pro) 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 allele was found at a frequency of 0.00034 in 118962 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 (0.00034 vs 0.0027), allowing no conclusion about variant significance. c.1577T>C has been reported in the literature in newborn screening studies (e.g. Donati_2018, Wasserstein_2019, Polo_2020, Bosfield_2021). One newborn in particular was found to be homozygous for this variant and exhibited urinary and dried blood spot glycosaminoglycan (GAG) levels within normal range (Donati_2018, Polo_2020). However, no follow-up data from a later stage of life were available to determine the actual phenotype. In contrast, a second homozygous individual was reported who had a clinical diagnosis of Mucopolysaccharidosis Type 1 with an attenuated phenotype (Zhang_2022). Importantly, the variant was also detected in combination with other known pathogenic variants in individuals affected with Mucopolysaccharidosis Type 1 (Pollard_2013, Dickson_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33098355, 31194252, 26260077, 30442156, 22976768, 32432561, 30093709, 35787971). ClinVar contains an entry for this variant (Variation ID: 567566). Based on the evidence outlined above, the variant was classified as likely pathogenic.
MGZ Medical Genetics Center RCV002289960 SCV002580801 likely pathogenic Mucopolysaccharidosis, MPS-I-H/S 2022-01-28 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001566840 SCV003809992 uncertain significance not provided 2024-01-11 criteria provided, single submitter clinical testing

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