Submissions for variant NM_000203.5(IDUA):c.266G>A (p.Arg89Gln)

gnomAD frequency: 0.00001  dbSNP: rs121965029

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000208598	SCV006101034	pathogenic	Mucopolysaccharidosis type 1	2025-04-07	reviewed by expert panel	curation	The NM_000203.5:c.266G>A variant in IDUA is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 89 (p.Arg89Gln). This variant accounts for up to 24% of alleles in Japanese individuals with MPS I (PMID: 8664897). At least 8 probands have been reported with the variant, typically with milder clinical features of MPS I and reduced IDUA activity (PMID: 8213840, 8664897, 2148086) (PP4). Of those individuals, 4 probands and one sibling, were compound heterozygous for the variant and variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP. None of those were confirmed in trans. The second variants is c.1205G>A (p.Trp402Ter) (PMID: 8213840, 2 patients, 2 x 0.5) and c.613_617dup (p.Glu207AlafsTer29) (PMID: 8664897, 2 probands, 0.5 x 2). Four individuals are homozygous for the variant (PMIDs: 8664897, 21480867, max 2 x 0.5 points). Total 3 points (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001662 (1/6016 alleles) in the Middle Eastern population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). This variant alters amino acid Arg89, a residue that has been shown to be important in the active site pocket and substrate binding in IDUA, and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (PMID: 14559116;15862278) (PM1). The computational predictor REVEL gives a score of 0.941 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 (PMID: 36413997) (PP3_Moderate). When expressed in CHO cells, the variant results in <5% WT activity (PMID: 14559116), and reduced amount of protein, and reduced specific activity (PMID: 14559116). Two other variants at the same amino acid position, c.265C>G (p.Arg89Gly) (ClinVar Variation ID: 2843836) and c.265C>T (p.Arg89Trp) (ClinVar Variation ID: 580286), have been reported. The evidence for pathogenicity for p.Arg89Gln will be used in the classification of the other two variants and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 11922). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Expert Panel (Specifications Version 1.0.0): PM3_strong, PM1, PP4, PP3_moderate, PM2_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 7, 2025).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000208598	SCV000919536	pathogenic	Mucopolysaccharidosis type 1	2018-03-22	criteria provided, single submitter	clinical testing	Variant summary: IDUA c.266G>A (p.Arg89Gln) results in a conservative amino acid change located in the Glycoside hydrolase superfamily of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 62804 control chromosomes (ExAC). The variant, c.266G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1. 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 reputable database, GeneReviews classifies the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000208598	SCV001422950	pathogenic	Mucopolysaccharidosis type 1	2020-01-13	criteria provided, single submitter	curation	The p.Arg89Gln variant in IDUA has been reported in at least 13 individuals with mucopolysaccharidosis (MPS), segregated with disease in 5 affected relatives from 2 families (PMID: 8213840, 8664897, 14559116, 28752568, 11735025, 21480867, and has been identified in 0.006% (1/16554) of East Asian chromosomes and 0.001% (1/94316) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965029). 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 been reported pathogenic in ClinVar by Integrated Genetics, OMIM, and GeneReviews (VariationID: 26961). In vitro functional studies provide some evidence that the p.Arg89Gln variant may impact protein function based on reduced protein levels in cells transfected with the variant (PMID: 14559116). However, these types of assays may not accurately represent biological function. The presence of this variant in 4 affected homozygotes and in combination with at least 1 reported pathogenic variant and in 2 individuals with MPS increases the likelihood that the p.Arg89Gln variant is pathogenic (VariationID: 11908; PMID: 8213840, 8664897, 14559116, 28752568). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for MPS based on significantly reduced alpha-L-iduronidase activity levels consistent with disease (PMID: 14559116). The p.Arg89Gln is located in the active site of IDUA, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 14559116, 15862278). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on multiple occurrences with pathogenic IDUA variants in individuals with MPS, in vitro functional studies, and low prevalence of the variant in the population. ACMG/AMP Criteria applied: PM3_strong, PM2, PM1, PS3_moderate, PP3, PM5_supporting, PP4, PP1 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000208598	SCV002233695	pathogenic	Mucopolysaccharidosis type 1	2023-06-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 89 of the IDUA protein (p.Arg89Gln). 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 (PMID: 8680403, 21462124, 29282708). ClinVar contains an entry for this variant (Variation ID: 11922). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005042034	SCV005672376	pathogenic	Mucopolysaccharidosis, MPS-I-S; Hurler syndrome; Mucopolysaccharidosis, MPS-I-H/S	2024-04-17	criteria provided, single submitter	clinical testing
OMIM	RCV000012697	SCV000032932	pathogenic	Mucopolysaccharidosis, MPS-I-H/S	1996-01-01	no assertion criteria provided	literature only
OMIM	RCV000169784	SCV000221749	pathogenic	Hurler syndrome	1996-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000208598	SCV000264378	pathogenic	Mucopolysaccharidosis type 1	2021-02-22	no assertion criteria provided	literature only	Common pathogenic variant in Japan; causes attenuated MPS I. May change ability of α-L-iduronidase to affect catalysis. Deleterious effect appears to be potentiated by a polymorphism, p.Ala361Thr
Natera, Inc.	RCV000208598	SCV001461749	pathogenic	Mucopolysaccharidosis type 1	2020-09-16	no assertion criteria provided	clinical testing