ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.223G>A (p.Ala75Thr) (rs758452450)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000670756 SCV000795651 pathogenic Hurler syndrome 2017-11-16 criteria provided, single submitter clinical testing
Invitae RCV000208613 SCV001223842 pathogenic Mucopolysaccharidosis type 1 2020-06-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 75 of the IDUA protein (p.Ala75Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs758452450, ExAC 0.004%). This variant has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 29843745, 16438163, 27146977, 8680403, 11735025). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 222993). This variant has been reported to affect IDUA protein function (PMID: 7550232). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000208613 SCV001362838 pathogenic Mucopolysaccharidosis type 1 2021-03-31 criteria provided, single submitter clinical testing Variant summary: IDUA c.223G>A (p.Ala75Thr) results in a non-conservative amino acid change located in the Glycoside hydrolase domain (IPR000514) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-06 in 241700 control chromosomes. c.223G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 (example, Clarke_1994, Ghosh_2017). 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 (example, Tieu_1995). Four clinical diagnostic laboratories and the Gene Reviews database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews RCV000208613 SCV000264377 pathogenic Mucopolysaccharidosis type 1 2016-02-11 no assertion criteria provided literature only
Broad Institute Rare Disease Group, Broad Institute RCV000208613 SCV001422947 pathogenic Mucopolysaccharidosis type 1 2020-01-13 no assertion criteria provided curation The p.Ala75Thr variant in IDUA has been reported in at least 9 individuals with mucopolysaccharidosis (MPS) (PMID: 29843745, 27146977, 28752568) and has been identified in 0.002% (3/121916) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs758452450). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (VariationID: 222993) as pathogenic by Counsyl and GeneReviews. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for MPS based on null alpha-L-iduronidase activity, consistent with disease (PMID: 27146977). The presence of this variant in 3 affected homozygotes and in combination with reported pathogenic and likely pathogenic variants in 5 individuals with MPS increases the likelihood that the p.Ala75Thr variant is pathogenic (VariationID: 11908, 11909; PMID: 29843745, 27146977, 28752568). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the presence of the variant in combination with other pathogenic or likely pathogenic variants in individuals with MPS and the phenotype of individuals with the variant being highly specific for MPS. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP3, PP4 (Richards 2015).
Natera, Inc. RCV000208613 SCV001461748 pathogenic Mucopolysaccharidosis type 1 2020-09-16 no assertion criteria provided clinical testing

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