Total submissions: 10
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000208594 | SCV005619853 | pathogenic | Mucopolysaccharidosis type 1 | 2024-12-06 | reviewed by expert panel | curation | The NM_000203.5(IDUA):c.152G>A variant in IDUA is predicted to result in a missense substitution, p.Gly51Asp. This variant has been reported in 9-13% of Italian MPS1 alleles (PMID: 9427149, 12203999, 21394825), and has been identified in patients from other European countries as well as Iran, Egypt, and India (PMID: 19839758, 31298590, 33301762). When reported, the diagnosis confirmed by deficiency of iduronidase activity (PMID: 7951228, 9427149, 12203999, 21394825) including one patient with detailed clinical features and residual enzyme activity values provided (PMID: 33301762) (PP4). At least 7 patients are homozygous for the variant (PMIDs: 9427149, 12203999, 19839758, 21394825, 31298590, 33301762). In addition, at least 6 patients are compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, all phase unknown, including c.208C>T (p.Gln70Ter) (2 patients, PMID: 12203999), c.1205G>A (p.Trp402Ter) (PMID: 7951228), and c.1598C>G (p.Pro533Arg) (at least 2 patients, PMID: 9427149, 12203999, 21394825), and c.1163delC (PMID: 12203999) (PM3_Very Strong). Further patients have been reported who are compound heterozygous for the variant but the allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic (PMID: 9427149, 12203999, 21394825). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002447 (2/81730 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.914 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PP3_Moderate). SpliceAI predicts no impact on splicing. There is a ClinVar entry for this variant (Variation ID: 193061). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PM3_Very Strong, PP3_Moderate, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) |
| Revvity Omics, |
RCV000723421 | SCV003818210 | pathogenic | not provided | 2021-12-16 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV002505243 | SCV002808762 | pathogenic | Mucopolysaccharidosis, MPS-I-S; Hurler syndrome; Mucopolysaccharidosis, MPS-I-H/S | 2024-05-08 | criteria provided, single submitter | clinical testing | |
| Broad Center for Mendelian Genomics, |
RCV000208594 | SCV001422978 | pathogenic | Mucopolysaccharidosis type 1 | 2020-01-13 | criteria provided, single submitter | 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). |
| Women's Health and Genetics/Laboratory Corporation of America, |
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. |
| Labcorp Genetics |
RCV000208594 | SCV000944986 | pathogenic | Mucopolysaccharidosis type 1 | 2024-01-22 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 51 of the IDUA protein (p.Gly51Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with mucopolysaccharidosis type I (MPS I) (PMID: 7951228, 9427149, 12203999, 19839758, 21394825). ClinVar contains an entry for this variant (Variation ID: 193061). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDUA protein function. For these reasons, this variant has been classified as Pathogenic. |
| Eurofins Ntd Llc |
RCV000723421 | SCV000224166 | pathogenic | not provided | 2015-06-01 | criteria provided, single submitter | clinical testing | |
| Natera, |
RCV000208594 | SCV001460713 | pathogenic | Mucopolysaccharidosis type 1 | 2020-09-16 | no assertion criteria provided | clinical testing | |
| Counsyl | RCV000173082 | SCV000793315 | pathogenic | Hurler syndrome | 2017-08-10 | 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 variantquestions@myriad.com. |
| Gene |
RCV000208594 | SCV000264389 | not provided | Mucopolysaccharidosis type 1 | no assertion provided | literature only | Common pathogenic variant in Italy |