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

gnomAD frequency: 0.00001  dbSNP: rs794726877

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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
Labcorp Genetics (formerly Invitae), Labcorp	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.
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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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).
Fulgent Genetics, Fulgent Genetics	RCV002505243	SCV002808762	pathogenic	Mucopolysaccharidosis, MPS-I-S; Hurler syndrome; Mucopolysaccharidosis, MPS-I-H/S	2022-05-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000723421	SCV003818210	pathogenic	not provided	2021-12-16	criteria provided, single submitter	clinical testing
GeneReviews	RCV000208594	SCV000264389	not provided	Mucopolysaccharidosis type 1		no assertion provided	literature only	Common pathogenic variant in Italy
Natera, Inc.	RCV000208594	SCV001460713	pathogenic	Mucopolysaccharidosis type 1	2020-09-16	no assertion criteria provided	clinical testing