Submissions for variant NM_000203.5(IDUA):c.1487C>G (p.Pro496Arg) (rs772416503)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000723457	SCV000700442	pathogenic	not provided	2017-03-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000592777	SCV000790464	pathogenic	Hurler syndrome	2017-03-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780349	SCV000917537	pathogenic	Mucopolysaccharidosis type 1	2018-04-24	criteria provided, single submitter	clinical testing	Variant summary: IDUA c.1487C>G (p.Pro496Arg) 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 was observed with an allele frequency of 1.4e-05 in 145584 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 (1.4e-05 vs 0.0027), allowing no conclusion about variant significance. The variant, c.1487C>G, has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 (Beesley_2001, Bertola_2011). 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. 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.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova	RCV000780349	SCV000929876	likely pathogenic	Mucopolysaccharidosis type 1	2019-01-01	criteria provided, single submitter	literature only	PS3: Low in vitro enzymatic activity. PM2: Very low frequency in ExAC. PP3: Multiple lines of computational evidence supporting a deleterious effect
Invitae	RCV000780349	SCV001204961	pathogenic	Mucopolysaccharidosis type 1	2019-04-18	criteria provided, single submitter	clinical testing	This sequence change replaces proline with arginine at codon 496 of the IDUA protein (p.Pro496Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs772416503, ExAC 0.007%). This variant has been observed in several individuals affected with Hurler syndrome (PMID: 21394825, 27520059). ClinVar contains an entry for this variant (Variation ID: 496861). This variant has been reported to affect IDUA protein function (PMID: 11735025). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group, Broad Institute	RCV000780349	SCV001422977	pathogenic	Mucopolysaccharidosis type 1	2020-01-13	no assertion criteria provided	curation	The p.Pro496Arg variant in IDUA has been reported in at least 13 individuals with mucopolysaccharidosis (MPS) (PMID: 21394825, 28752568, 27520059) and has been identified in 0.003% (2/66872) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs772416503). 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 has also been reported in ClinVar (VariationID: 496861) as pathogenic by Counsyl, EGL Genetic Diagnostics, and Integrated Genetics. In vitro functional studies provide some evidence that the p.Pro496Arg variant may impact protein function (PMID: 11735025). 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 presence of this variant in combination with reported pathogenic variants and in at least 8 individuals with MPS increases the likelihood that the p.Pro496Arg variant is pathogenic (VariationID: 193061, 11909, 11908; PMID: 21394825, 28752568). One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Pro496Leu, has been reported in association with disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 7550232; Variation ID: 551675). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on its presence in combination with other pathogenic variants in individuals with MPS and functional studies. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PS3_moderate, PP3 (Richards 2015).
Natera, Inc.	RCV000780349	SCV001461767	pathogenic	Mucopolysaccharidosis type 1	2020-09-16	no assertion criteria provided	clinical testing