Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003499497 | SCV004337023 | likely pathogenic | Multiple congenital exostosis | 2023-10-30 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 346 of the EXT1 protein (p.Arg346Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary multiple osteochondromas (Invitae). 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 EXT1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg346 amino acid residue in EXT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17301954, 19810120, 24532482). 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. |