Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000494520 | SCV000581904 | uncertain significance | not provided | 2017-05-05 | criteria provided, single submitter | clinical testing | The P357R variant in the EXT1 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P357R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether P357R is a pathogenic variant or a rare benign variant. We consider it to be a variant of uncertain significance. |
| Invitae | RCV001856960 | SCV002291151 | likely pathogenic | Multiple congenital exostosis | 2021-02-13 | criteria provided, single submitter | clinical testing | 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. 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. This variant has been observed in individual(s) with clinical features of hereditary multiple osteochondromas (Invitae). ClinVar contains an entry for this variant (Variation ID: 429353). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with arginine at codon 357 of the EXT1 protein (p.Pro357Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. |