Submissions for variant NM_000203.5(IDUA):c.713T>A (p.Leu238Gln)

gnomAD frequency: 0.00002  dbSNP: rs148789453

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000256027	SCV000322294	pathogenic	not provided	2022-08-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the L238Q variant causes reduced IDUA activity and protein levels when expressed in Chinese hamster ovary (CHO) cells (Yogalingam et al., 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15300847, 24368159, 26260077, 31194252)
Counsyl	RCV000668680	SCV000793321	likely pathogenic	Hurler syndrome	2017-08-10	criteria provided, single submitter	clinical testing
Invitae	RCV000802940	SCV000942791	pathogenic	Mucopolysaccharidosis type 1	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 238 of the IDUA protein (p.Leu238Gln). This variant is present in population databases (rs148789453, gnomAD 0.008%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 15300847, 24368159; Invitae). ClinVar contains an entry for this variant (Variation ID: 265418). 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%. This variant disrupts the p.Leu238 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been observed in individuals with IDUA-related conditions (PMID: 21480867, 24368159), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000802940	SCV001422676	pathogenic	Mucopolysaccharidosis type 1	2020-01-14	criteria provided, single submitter	curation	The p.Leu238Gln variant in IDUA has been reported in at least 7 individuals with mucopolysaccharidosis (MPS), segregated with disease in 4 affected relatives from 2 families (PMID: 24368159), and has been Identified in 0.014% (2/13914) of African chromosomes and 0.003% (3/102956) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148789453). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Leu238Gln variant may impact protein function (PMID: 15300847). 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 in 5 individuals with MPS increases the likelihood that the p.Leu238Gln variant is pathogenic (VariationID: 11908, 222994; PMID: 24368159). The phenotype of individuals compound heterozygous for this variant is highly specific for MPS based on alpha-L-iduronidase activity being <1%, consistent with disease (PMID: 15300847). 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 known pathogenic variants, functional studies, cosegregation, and the phenotype of individuals with the variant and MPS being highly specific for IDUA. ACMG/AMP Criteria applied: PM3_strong, PS3_moderate, PM2_supporting, PP3, PP4, PP1 (Richards 2015).
Revvity Omics, Revvity	RCV000256027	SCV002023100	pathogenic	not provided	2020-11-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000802940	SCV001461754	pathogenic	Mucopolysaccharidosis type 1	2020-09-16	no assertion criteria provided	clinical testing