Submissions for variant NM_000203.5(IDUA):c.544G>A (p.Glu182Lys)

gnomAD frequency: 0.00001  dbSNP: rs754154200

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV002629390	SCV005619867	pathogenic	Mucopolysaccharidosis type 1	2024-12-06	reviewed by expert panel	curation	The NM_000203.5:c.544G>A variant in IDUA is predicted to result in the missense substitution of glutamine by lysine at amino acid 182 (p.Glu182Lys). This residue, Glu182 is one of the active site residues of IDUA; a role that has been shown by multiple homology modeling, crystallography, and functional studies (PMID: 11555618, 15862278, 23959878, 24036510, 24480078). Two patients with MPS 1 have been reported with the variant but there is insufficient evidence to apply PP4. One of these patients, with severe MPS 1 is compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, c.1205G>A (p.Trp402Ter) (ClinGen Variation ID: 11908). The phase is unknown (PMID: 11555618, 12559846). Another patient, with attenuated symptoms, is compound heterozygous for the variant and c.712T>A (p.Leu238Gln); The allelic data for this patient will be used in the assessment of p.Leu238Gln and is not included here to avoid circular logic. (PM3_Supporting). As noted, Glu182 has been shown to be important in the active site of IDUA, and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (PMID: 23959878, 24036510, 24480078) (PM1). When expressed in CHO cells and HAP1 cells , the variant resulted in no IDUA activity across multiple studies (PMID: 11555618, 12559846, 33198351) (PS3_Supporting). The computational predictor REVEL gives a score of 0.928 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). The highest population minor allele frequency in gnomAD v4.1.0 is 8.475e-7 (1/1179960 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). Other missense substitutions at the same amino acid have been reported in affected individuals, including c.546G>C (p.Glu182Asp) (PMID: 21480867), and c.544G>C (p.Glu182Gln) (homozygous individual reported in the Iran Variome MPS Database, https://variome.ir/lovd/genes/IDUA). The LD VCEP has not yet classified these variants and therefore, this data will not be used to support the classification of c.544G>A (p.Glu182Lys). There is a ClinVar entry for this variant (Variation ID: 2198440). The classification has been modified from likely pathogenic to pathogenic based on extensive evidence showing that Glu182 is an active site residue, with multiple functional, crystallography, and modeling studies (stacking evidence). In summary, these 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 Variant Curation Expert Panel (Specifications Version 1.0.0): PM1, PP3_Moderate, PS3_Supporting, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002629390	SCV003518706	likely pathogenic	Mucopolysaccharidosis type 1	2022-10-18	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Glu182 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been observed in individuals with IDUA-related conditions (PMID: 21480867), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects IDUA function (PMID: 11555618, 33198351). 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. This missense change has been observed in individuals with mucopolysaccharidosis type I (PMID: 11555618, 24368159). This variant is present in population databases (rs754154200, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 182 of the IDUA protein (p.Glu182Lys).
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV004820929	SCV005441982	likely pathogenic	Hurler syndrome	2024-12-19	criteria provided, single submitter	clinical testing