Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratorio de Citogenómica y Microarreglos, |
RCV001293240 | SCV001443261 | pathogenic | Sialidosis type 2 | 2020-11-17 | criteria provided, single submitter | research | As previously predicted, the Y370C variant alters the tridimensional structure of the active site of the enzyme, eliminating the benzyl ring and hydroxyl group of this well-preserved amino acid residue. This tyrosine residue stabilizes the transition of a carbonium ion intermediate during catalysis. The crystal structure of a bacterial sialidase (from Salmonella typhimurium LT2) shows the same fold as an influenza virus neuraminidase [Crennell et al., 1993] and its loss leads to an unactive enzyme that still localizes to the lysosome [Bonten et al., 2000]. In our in silico analysis, which was generated based on the crystal structure of the Streptococcus pneumoniae neuraminidase (access no. 2w20) and where both the energy minimization and structure fitting were achieved using the Swiss-model software suite [Guex et al., 2009; Artimo P et al., 2012], we show that the Y370C substitution introduces a side chain incapable of reaching into the active site pocket formed by well-conserved arginine (R76, R278 and R339) and glutamate (E392 and E262) residues, thus leading to the inability of the cysteine residue to stabilize the transition state of the substrate. This leads to a suppression of the catalytic activity of the Y370C mutant product [Bonten et al. 2000]. This variant was also reported in two other sialidosis patients. |
| Invitae | RCV002542852 | SCV003260042 | pathogenic | not provided | 2023-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 370 of the NEU1 protein (p.Tyr370Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with sialidosis (PMID: 11063730, 34421504). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1107A>G. ClinVar contains an entry for this variant (Variation ID: 986732). 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 NEU1 protein function. Experimental studies have shown that this missense change affects NEU1 function (PMID: 11063730). For these reasons, this variant has been classified as Pathogenic. |