Submissions for variant NM_000203.5(IDUA):c.1046A>G (p.Asp349Gly)

gnomAD frequency: 0.00004  dbSNP: rs371397270

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001222699	SCV001394813	pathogenic	Mucopolysaccharidosis type 1	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 349 of the IDUA protein (p.Asp349Gly). This variant is present in population databases (rs371397270, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of mucopolysaccharidosis type I (Invitae). 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: 950889). 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.Asp349 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12203999, 12559846, 28752568, 30809705). 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.
GeneDx	RCV001586065	SCV001821075	likely pathogenic	not provided	2019-03-05	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign in a patient with mucopolysaccharidosis type I to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28676128)
Revvity Omics, Revvity	RCV001586065	SCV003830031	likely pathogenic	not provided	2023-12-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001222699	SCV004030089	likely pathogenic	Mucopolysaccharidosis type 1	2023-07-27	criteria provided, single submitter	clinical testing	Variant summary: IDUA c.1046A>G (p.Asp349Gly) 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 1.2e-05 in 248312 control chromosomes (gnomAD). c.1046A>G has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1 (example: Can_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants affecting the same residue have been classified pathogenic in ClinVar (CV IDs 638075, 92623) suggesting this residue may be critical for normal function of the protein. The following publication has been ascertained in the context of this evaluation (PMID: 34833038). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.