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

gnomAD frequency: 0.00001  dbSNP: rs772416503

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000780349	SCV005903283	likely pathogenic	Mucopolysaccharidosis type 1	2024-12-05	reviewed by expert panel	curation	The NM_000203.5:c.1487C>G variant in IDUA is a missense variant predicted to cause substitution of Proline by Arginine at amino acid 496 p.(Pro496Arg). At least 8 patients are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP including c.793G>C (p.Gly265Arg) (ClinVar Variation ID: 638074) (PMID: 21394825, LP, 0.25), c.152G>A (p.Gly51Asp) (ClinVar Variation ID: 193061) (PMID: 21394825, P, 2 x 0.5), c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (PMID: 21394825, P, 4 patients, max 2 x 0.5), and c.1598C>G (p.Pro533Arg) (PMID: 34408967, P, 0.5 points). One individual is homozygous for the variant (PMID: 34408967, 0.5 points). This variant has also been reported in compound heterozygosity with p.Arg89Trp (PMID: 21394825), c.1727+1G>A (PMID: 21394825), c.1854C>A (p.Tyr618Ter) (PMID: 27520059) and c.878_889dup (PMID 28752568). The allelic data from these patients will be used in the subsequent classification of then second variant and is not included here to avoid circular logic. Total 3.25 points (PM3_Strong). In one report (PMID: 27520059), there was evidence of decreased IDUA enzyme activity, increased urine glycosaminoglycans and a specific clinical phenotype, allowing for application of PP4_Moderate. The highest population minor allele frequency in gnomAD v4.1.0. is 0.000003515 (4/1137936 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). and has some experimental evidence suggesting absence of IDUA activity when the variant is expressed in Cos-7 cells (PMID: 11735025) (PS3_Supporting). Computational predictor tools (REVEL score 0.72) suggest that this variant may be deleterious to IDUA function (PP3). A different missense variant, c.1487C>G (p.Pro496Leu) [ClinVar Variation ID 551675] in the same codon has been classified as likely pathogenic for MPS I by the ClinGen VCEP, however PM5 was not assigned to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 496861). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel: PM3_Strong, PP4_Moderate. PS3_Supporting, PM2_Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024)
Eurofins Ntd Llc (ga)	RCV000723457	SCV000700442	pathogenic	not provided	2017-03-30	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000780349	SCV001204961	pathogenic	Mucopolysaccharidosis type 1	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 496 of the IDUA protein (p.Pro496Arg). This variant is present in population databases (rs772416503, gnomAD 0.003%). This missense change has been observed in individual(s) with Hurler syndrome (PMID: 21394825, 27520059). ClinVar contains an entry for this variant (Variation ID: 496861). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IDUA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects IDUA function (PMID: 11735025). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000780349	SCV001422977	pathogenic	Mucopolysaccharidosis type 1	2020-01-13	criteria provided, single submitter	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).
Revvity Omics, Revvity	RCV000723457	SCV003818222	pathogenic	not provided	2022-07-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005044877	SCV005667785	likely pathogenic	Mucopolysaccharidosis, MPS-I-S; Hurler syndrome; Mucopolysaccharidosis, MPS-I-H/S	2024-05-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000592777	SCV000790464	pathogenic	Hurler syndrome	2017-03-21	no assertion criteria provided	clinical testing	This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact [e-mail].
Natera, Inc.	RCV000780349	SCV001461767	pathogenic	Mucopolysaccharidosis type 1	2020-09-16	no assertion criteria provided	clinical testing