Submissions for variant NM_000203.5(IDUA):c.536C>T (p.Thr179Met)

gnomAD frequency: 0.00004  dbSNP: rs776098539

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001942261	SCV005619863	likely pathogenic	Mucopolysaccharidosis type 1	2024-12-06	reviewed by expert panel	curation	The NM_000203.5:c.536C>T variant in IDUA is predicted to result in a missense substitution, p.Thr179Met. One patient is compound heterozyous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1205G>A or (p.Trp402Ter); the variants were identified by trio exome sequencing are are confirmed to be in trans (PMID: 32670797) (PM3). This patient has documented values showing deficient IDUA activity in two independent samples, elevated urine GAGs with high levels of heparan and dermatan sulfate which reduced to only a trace after 12 months of enzyme replacement therapy, and clinical symptoms consistent with the condition (PMID: 32670797) (PP4_Moderate). The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.0002 (5/25114 alleles) in the Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion. The next highest population MAF is 0.00003 (4/128740 alleles) in the European non-Finnish population (PM2_Supporting). Other missense variants at the same position have been reported in individuals with MPS1, including c.536C>G (p.Thr179Arg) (PMID: 21480867), and p.Thr179Lys (PMID: 28752568). The classification of c.536C>T (p.Thr179Met) will be used in the assessment of the other variants at Thr179 and is not included here to avoid circular logic. There is a ClinVar entry for this variant (ClinVar ID: 1455223). In summary, this variant meets the criteria to be classified as likely pathogenic. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM3, PP3_Moderate, PP4_Moderate, PM2_Supporting (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001942261	SCV002232692	pathogenic	Mucopolysaccharidosis type 1	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 179 of the IDUA protein (p.Thr179Met). This variant is present in population databases (rs776098539, gnomAD 0.02%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 32670797). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1455223). 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.Thr179 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21480867, 28752568). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV003130637	SCV003817650	likely pathogenic	not provided	2023-06-28	criteria provided, single submitter	clinical testing
GeneDx	RCV003130637	SCV003933472	likely pathogenic	not provided	2023-06-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32670797, 21480867)