Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002038611 | SCV002312718 | likely pathogenic | Sandhoff disease | 2021-01-11 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with HEXB-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 HEXB protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.His235 amino acid residue in HEXB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23127958). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 sequence change replaces histidine with glutamine at codon 235 of the HEXB protein (p.His235Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. |