Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000669494 | SCV000794251 | uncertain significance | Mucopolysaccharidosis, MPS-III-B | 2017-09-20 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001855520 | SCV002275145 | likely pathogenic | Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V | 2023-09-01 | criteria provided, single submitter | clinical testing | 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 NAGLU protein function. ClinVar contains an entry for this variant (Variation ID: 553948). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 14984474). 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 sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 482 of the NAGLU protein (p.Arg482Gln). Experimental studies have shown that this missense change affects NAGLU function (PMID: 14984474, 29979746). 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.Arg482 amino acid residue in NAGLU. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9950362, 12202988, 16151907, 16447797, 23667853, 28018442). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. |
| Gene |
RCV003227824 | SCV003924967 | likely pathogenic | not provided | 2022-11-15 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate reduced enzyme activity (Beesley et al., 2004; Clark et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); 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: 26659599, 29979746, 14984474) |