Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001062380 | SCV001227177 | pathogenic | Mucopolysaccharidosis type 1 | 2023-11-06 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 423 of the IDUA protein (p.Ser423Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 15300847, 21394825, 31194252). 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: 856833). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDUA protein function. Experimental studies have shown that this missense change affects IDUA function (PMID: 15300847). For these reasons, this variant has been classified as Pathogenic. |
| Revvity Omics, |
RCV001784619 | SCV002016670 | likely pathogenic | not provided | 2021-07-29 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001062380 | SCV002500297 | likely pathogenic | Mucopolysaccharidosis type 1 | 2022-03-10 | criteria provided, single submitter | clinical testing | Variant summary: IDUA c.1269C>A (p.Ser423Arg) 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 2.8e-05 in 71888 control chromosomes (gnomAD). The variant c.1269C>A has been reported in the literature in homozygous state in an individual affected with Mucopolysaccharidosis Type 1 (Bertola_2011), who had a diagnosis confirmed biochemically by demonstrating a defect of IDUA activity, however this patient was also noted to carry another missense variant (c.562T>C/p.Phe188Leu) in homozygous state. An equivalent protein level variant (c.1269C>G (p.S423R)) has been also reported in an affected compound heterozygous patient (Yogalingam_2004), and the variant, p.S423R (described only at the protein level) was also found in an independent compound heterozygous patient (Clarke_2019). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated a severely reduced protein level and enzyme activity for the Ser423Arg variant protein expressed in mammalian cells (Yogalingam_2004). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Fulgent Genetics, |
RCV002482062 | SCV002788964 | likely pathogenic | Mucopolysaccharidosis, MPS-I-S; Hurler syndrome; Mucopolysaccharidosis, MPS-I-H/S | 2021-08-11 | criteria provided, single submitter | clinical testing |