ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.1174C>T (p.Leu392=) (rs201682298)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000288834 SCV000451785 benign Mucopolysaccharidosis type 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000591138 SCV000700304 benign not specified 2017-02-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000591138 SCV000919537 benign not specified 2018-04-16 criteria provided, single submitter clinical testing Variant summary: IDUA c.1174C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.011 in 169258 control chromosomes in the gnomAD database, including 20 homozygotes. The observed variant frequency is approximately 4.26 fold of the estimated maximal expected allele frequency for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 phenotype (0.0027), strongly suggesting that the variant is benign. c.1174C>T has not been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1, on the other hand it was reported to be found in healthy controls and described as a polymorphism (Bertola 2011, Scott 1995). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; one of these laboratories classified the variant as benign, the other laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000288834 SCV001640514 likely benign Mucopolysaccharidosis type 1 2020-12-05 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000675608 SCV000801306 likely benign not provided 2017-04-18 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000288834 SCV001422671 benign Mucopolysaccharidosis type 1 2020-01-13 no assertion criteria provided curation The c.1174C>T (p.Leu392=) variant in IDUA has not been previously reported in individuals with mucopolysaccharidosis but has been identified in 1.964% (1347/68572) of European (non-Finnish) chromosomes, including 14 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201682298). This variant has also been reported in ClinVar (VariationID: 350229) as a VUS by Illumina Clinical Services Laboratory, likely benign by Mayo Clinical Testing Laboratories, and benign by EGL Genetic Diagnostics and Integrated Genetics. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, this variant meets criteria to be classified as benign for mucopolysaccharidosis in an autosomal recessive manner based on its frequency in the general population and multiple reports of unaffected homozygotes. ACMG/AMP Criteria applied: BS1, BS2, BP4, BP7 (Richards 2015).

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