ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.493+6C>G

dbSNP: rs376738689
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001247275 SCV001420687 uncertain significance Mucopolysaccharidosis type 1 2022-11-01 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the IDUA gene. It does not directly change the encoded amino acid sequence of the IDUA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs376738689, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with IDUA-related conditions. ClinVar contains an entry for this variant (Variation ID: 971485). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
PreventionGenetics, part of Exact Sciences RCV003945944 SCV004758596 likely benign IDUA-related disorder 2019-12-17 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003987812 SCV004804515 uncertain significance not specified 2024-01-12 criteria provided, single submitter clinical testing Variant summary: IDUA c.493+6C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-05 in 249238 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 (8e-05 vs 0.0027), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.493+6C>G in individuals affected with Mucopolysaccharidosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 971485). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV001247275 SCV002075290 uncertain significance Mucopolysaccharidosis type 1 2020-04-22 no assertion criteria provided clinical testing

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