ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.613_617dup (p.Glu207fs) (rs786200915)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000012696 SCV000795133 pathogenic Hurler syndrome 2017-10-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000208610 SCV000917540 pathogenic Mucopolysaccharidosis type 1 2018-06-22 criteria provided, single submitter clinical testing Variant summary: IDUA c.613_617dupTGCTC (p.Glu207AlafsX29) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.8e-06 in 227460 control chromosomes (gnomAD). The variant, c.613_617dupTGCTC, has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 (Ghosh_2017, Kwak_2016, Yamagishi_1996). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Kwak_2016). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000208610 SCV001376850 pathogenic Mucopolysaccharidosis type 1 2019-06-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu207Alafs*29) in the IDUA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with mucopolysaccharidosis type I (PMID: 8664897, 27520059, 29620724). This variant is also known as 704ins5 in the literature. ClinVar contains an entry for this variant (Variation ID: 11921). Loss-of-function variants in IDUA are known to be pathogenic (PMID: 11735025, 21480867). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000012696 SCV000032931 pathogenic Hurler syndrome 2004-12-01 no assertion criteria provided literature only
GeneReviews RCV000208610 SCV000264388 pathogenic Mucopolysaccharidosis type 1 2016-02-11 no assertion criteria provided literature only
Broad Institute Rare Disease Group, Broad Institute RCV000208610 SCV001422944 pathogenic Mucopolysaccharidosis type 1 2020-01-13 no assertion criteria provided curation The p.Glu207AlafsTer29 variant in IDUA has been reported in least 7 individuals with mucopolysaccharidosis (MPS) (PMID: 8664897, 27520059) and has been identified in 0.011% (2/17752) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs786200915). 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 is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 207 and leads to a premature termination codon 29 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the IDUA gene is an established disease mechanism in autosomal recessive MPS. The presence of this variant in 2 affected homozygotes and in combination with a reported pathogenic variant in at least 3 individuals with MPS increases the likelihood that the p.Glu207AlafsTer29 variant is pathogenic (VariationID: 11922; PMID: 8664897). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the prediction that the variant will cause loss of function and the presence of the variant in combination with known pathogenic variants in individuals with MPS. ACMG/AMP Criteria applied: PVS1, PM3_strong, PM2_supporting (Richards 2015).

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