ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.1090A>G (p.Thr364Ala)

dbSNP: rs1216054018
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV002039017 SCV005903284 uncertain significance Mucopolysaccharidosis type 1 2024-12-05 reviewed by expert panel curation The NM_000203.5:c.1090A>G variant in IDUA is a missense variant predicted to cause substitution of threonine by alanine at amino acid 364 (p.Thr364Ala). To our knowledge, this variant has not been reported in the literature in any individuals with MPS I and no results of functional assays are available. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001104 (1/90550 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.875 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). Another missense variant c.1091C>T (p.Thr364Met) (ClinVar Variation ID: 11925) in the same codon has been classified as pathogenic for MPS I by the ClinGen Lysosomal Diseases VCEP (PM5). In summary, this variant meets the criteria to be classified as a VUS for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PM2_Supporting, PP3_Moderate, PM5. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024)
Labcorp Genetics (formerly Invitae), Labcorp RCV002039017 SCV002313709 uncertain significance Mucopolysaccharidosis type 1 2021-04-06 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 364 of the IDUA protein (p.Thr364Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with IDUA-related conditions. 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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