ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.152G>A (p.Gly51Asp) (rs794726877)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723421 SCV000224166 pathogenic not provided 2015-06-01 criteria provided, single submitter clinical testing
Counsyl RCV000173082 SCV000793315 pathogenic Hurler syndrome 2017-08-10 criteria provided, single submitter clinical testing
Invitae RCV000208594 SCV000944986 pathogenic Mucopolysaccharidosis type 1 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 51 of the IDUA protein (p.Gly51Asp). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and aspartic acid. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in several individuals affected with mucopolysaccharidosis type I (MPS I) and is considered a common disease-causing variant in individuals of Mediterranean descent (PMID: 7951228, 9427149, 12203999, 19839758, 21394825). ClinVar contains an entry for this variant (Variation ID: 193061). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000208594 SCV001362836 pathogenic Mucopolysaccharidosis type 1 2019-07-16 criteria provided, single submitter clinical testing Variant summary: IDUA c.152G>A (p.Gly51Asp) 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 9.2e-06 in 109252 control chromosomes (gnomAD). c.152G>A has been reported in the literature in multiple individuals (both homozygous and compound heterozygous) affected with Mucopolysaccharidosis Type 1 (Bertola_2011, Bunge_1994, Amr_2009). Many of these patients, had a severe phenotype. These data indicate that the variant is very likely to be associated with disease. Three ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews RCV000208594 SCV000264389 pathogenic Mucopolysaccharidosis type 1 2016-02-11 no assertion criteria provided literature only
Broad Institute Rare Disease Group, Broad Institute RCV000208594 SCV001422978 pathogenic Mucopolysaccharidosis type 1 2020-01-13 no assertion criteria provided curation The p.Gly51Asp variant in IDUA has been reported in at least 15 individuals with mucopolysaccharidosis (MPS) (PMID: 7951228, 19839758, 12203999, 21394825) and has been identified in 0.002% (1/40612) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs794726877). 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: 193061) as pathogenic by EGL Genetic Diagnostics, Counsyl, and GeneReviews. In vitro functional studies provide some evidence that the p.Gly51Asp variant may slightly impact protein function (PMID: 9748610). However, these types of assays may not accurately represent biological function. 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 an individual compound heterozygous for this variant is highly specific for MPS based on significantly reduced alpha-L-iduronidase activity levels consistent with disease (PMID: 9748610). Additionally, the presence of this variant in at least 3 affected homozygotes and in combination with reported pathogenic variants in at least 8 individuals with MPS increases the likelihood that the p.Gly51Asp variant is pathogenic (VariationID: 11908, 11909, 11910, 496861; PMID: 7951228, 19839758, 12203999, 21394825). 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 variants in individuals with MPS, functional studies, and the phenotype of patients with the variant being highly specific for IDUA. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP3, PP4, PS3_supporting (Richards 2015).
Natera, Inc. RCV000208594 SCV001460713 pathogenic Mucopolysaccharidosis type 1 2020-09-16 no assertion criteria provided clinical testing

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